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1 Henry C. Su (SBN 211202; [email protected]) Katharine L. Altemus (SBN 227080; [email protected]) 2 HOWREY LLP 1950 University Avenue, 4th Floor 3 East Palo Alto, California 94303 Telephone: (650) 798-3500 4 Facsimile: (650) 798-3600 5 Robert Ruyak Matthew Wolf 6 Marc Cohn HOWREY LLP 7 1229 Pennsylvania Avenue, NW Washington, DC 20004 8 Telephone: (202) 783-0800 Facsimile: (202) 383-6610 9 Attorneys for Plaintiffs 10 HOLOGIC, INC., CYTYC CORPORATION and HOLOGIC LP 11 12 13 UNITED STATES DISTRICT COURT NORTHERN DISTRICT OF CALIFORNIA SAN JOSE DIVISION Case No. C08 00133 RMW (RS) DECLARATION OF KATHARINE L. ALTEMUS IN SUPPORT OF PLAINTIFFS' REPLY BRIEF IN SUPPORT OF MOTION FOR PRELIMINARY INJUNCTION
14 HOLOGIC, INC., CYTYC CORPORATION, and HOLOGIC L.P., 15 Plaintiffs, 16 vs. 17 SENORX, INC., 18 Defendant. 19 20 21 AND RELATED COUNTERCLAIMS. 22 23 24 25 26 27 28
HOWREY LLP
Date: April 21, 2008 Time: 2:00 p.m. Courtroom: 6, 4th Floor Judge: Hon. Ronald M. Whyte
Case 5:08-cv-00133-RMW
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I, Katharine L. Altemus, declare that I am an associate in the law firm Howrey LLP and a
2 member of the bar of this court, and I serve as one of the outside counsel for Plaintiffs Hologic, Inc., 3 Cytyc Corporation and Hologic LP. The following declaration is based on my personal knowledge, 4 and if sworn as a witness I could and would competently testify as to the matters set forth herein. 5 1. Attached hereto as Exhibit O is a true and correct copy of a document produced in this
6 litigation by Defendant, Bates numbered SRX-HOL00006590-611, marked Confidential-Outside 7 Counsel Only and submitted under seal. 8 2. Attached hereto as Exhibit P is a true and correct copy of United States Patent No.
9 6,413,204. 10 3. Attached hereto as Exhibit Q is a true and correct copy of a document produced in this
11 litigation by Defendant, Bates numbered SRX-HOL00004119-128, marked Confidential-Outside 12 Counsel Only and submitted under seal. 13 4. Attached hereto as Exhibit R is a true and correct copy of a document produced in this
14 litigation by Defendant, Bates numbered SRX-HOL00006486-497, marked Confidential-Outside 15 Counsel Only and submitted under seal. 16 5. Attached hereto as Exhibit S is a true and correct copy of a document produced in this
17 litigation by Defendant, Bates numbered SRX-HOL00000314-318. 18 6. Attached hereto as Exhibit T is a true and correct copy of an article by R.D. Ashpole, et
19 al., entitled "A New Technique of Brachytherapy for Malignant Gliomas with Caesium-173: A New 20 Method Utilizing a Remote Afterloading System," produced in this litigation by Defendant, Bates 21 numbered SRX-HOL00002292-296. 22 7. Attached hereto as Exhibit U is a true and correct copy of excerpts from the transcript of
23 the deposition of Colin G. Orton, Ph. D. taken on April 4, 2008, marked Highly Confidential and 24 submitted under seal. 25 26 8. 9. Attached hereto as Exhibit V is a true and copy of United States Patent No. 6,482,142. Attached hereto as Exhibit W is a true and correct copy of a document produced in this
27 litigation by Defendant, Bates numbered SRX-HOL00006616-686, marked Confidential-Outside 28 Counsel Only, and submitted under seal.
HOWREY LLP
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1
10.
Attached hereto as Exhibit X is a true and correct copy of a document produced in this
2 litigation by Defendant, Bates numbered SRX-HOL00007335-7348, marked Confidential-Outside 3 Counsel Only, and submitted under seal. 4 11. Attached hereto as Exhibit Y is a true and correct copy of excerpts from the transcript of
5 the deposition of William F. Gearhart, taken on April 2, 2008, marked Confidential and submitted 6 under seal. 7 12. Attached hereto as Exhibit Z is a true and correct copy of excerpts from the transcript of
8 the deposition of Philip Z. Israel, taken on April 2, 2008. 9 13. Attached hereto as Exhibit AA is a true and correct copy of a document produced in this
10 litigation by Defendant, Bates numbered SRX-HOL00007202-205, marked Confidential-Outside 11 Counsel Only, and submitted under seal. 12 14. Attached hereto as Exhibit BB is a true and correct copy of a document produced in this
13 litigation by Defendant, Bates numbered SRX-HOL00007169-187, marked Confidential-Outside 14 Counsel Only, and submitted under seal. 15 15. Attached hereto as Exhibit CC is a true and correct copy of a document produced in this
16 litigation by Defendant, Bates numbered SRX-HOL00007192-201, marked Confidential-Outside 17 Counsel Only, and submitted under seal. 18 16. Attached hereto as Exhibit DD is a true and correct copy of a document produced in this
19 litigation by Defendant, Bates numbered SRX-HOL00007323-334, marked Confidential-Outside 20 Counsel Only, and submitted under seal. 21 17. Attached hereto as Exhibit EE is a true and correct copy of excerpts from the transcript
22 of the deposition of Hologic, Inc. taken on March 18, 2008, pursuant to Fed.R.Civ.P. 30(b)(6), through 23 Glenn I. Magnuson, marked Confidential, and submitted under seal. 24 18. Attached hereto as Exhibit FF is a true and correct copy of excerpts from the transcript
25 of the deposition of Roy Weinstein taken on April 4, 2008, marked Highly Confidential, and submitted 26 under seal. 27 28
HOWREY LLP
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19.
Attached hereto as Exhibit GG is a true and correct copy of a document produced in this
2 litigation by Defendant, Bates numbered SRX-HOL00006575-584, marked Confidential-Outside 3 Counsel Only, and submitted under seal. 4 20. Attached hereto as Exhibit HH is a true and correct copy of excerpts from the transcript
5 of the deposition of Douglas W. Arthur taken on April 4, 2008, marked Highly Confidential, and 6 submitted under seal. 7 21. Attached hereto as Exhibit II is a true and correct copy of a document produced in this
8 litigation by Defendant, Bates numbered SRX-HOL00007316-322, marked Confidential-Outside 9 Counsel Only, and submitted under seal. 10 22. Attached hereto as Exhibit JJ is a true and correct copy of a document produced in this
11 litigation by Defendant, Bates numbered SRX-HOL 00002232-233. 12 23. Attached hereto as Exhibit KK is a true and correct copy of a document produced in this
13 litigation by Defendant, Bates numbered SRX-HOL00005395-429, marked Confidential-Outside 14 Counsel Only, and submitted under seal. 15 24. Attached hereto as Exhibit LL is a true and correct copy of a document produced in this
16 litigation by Defendant, Bates numbered SRX-HOL5538, marked Confidential-Outside Counsel Only, 17 and submitted under seal. 18 25. Attached hereto as Exhibit MM is a true and correct copy of excerpts from the transcript
19 of the deposition of Ronald E. Cahill taken on April 18, 2007, in the matter of Xoft Microtube, Inc. v. 20 Cytyc Corporation, a Delaware corporation, and Proxima Therapeutics, Inc., a Delaware 21 corporation, filed in the United States District Court, Northern District of California, Civil Action No. 22 CV 05-05312 RMW. 23 26. Attached hereto as Exhibit NN is a true and correct copy of a document produced in this
24 litigation by Defendant, Bates numbered SRX-HOL00005563-65, marked Confidential-Outside 25 Counsel Only, and submitted under seal. 26 27. Attached hereto as Exhibit OO is a true and correct copy of Claim Construction Order
27 filed April 27, 2007, in the matter of Xoft Microtube, Inc. v. Cytyc Corporation, a Delaware 28
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1 corporation, and Proxima Therapeutics, Inc., a Delaware corporation, filed in the United States 2 District Court, Northern District of California, Civil Action No. CV 05-05312 RMW. 3 28. Attached hereto as Exhibit PP is a true and correct copy of a document produced in this
4 litigation by Defendant, Bates numbered SRX-HOL00000211-224. 5 29. Attached hereto as Exhibit QQ is a true and correct copy of a document produced in this
6 litigation by Defendant, Bates numbered SRX-HOL00005492, marked Confidential-Outside Counsel 7 Only, and submitted under seal. 8 30. Attached hereto as Exhibit RR is a true and correct copy of the cover page, table of
9 contents page i, and pages 37, 38 and 39 of Form 10-K, Annual Report Pursuant to Section 13 or 15(d) 10 of the Securities Exchange Act of 1934, for the fiscal year ended December 31, 2007, filed by 11 Defendant with the United States Securities and Exchange Commission. 12 31. Attached hereto as Exhibit SS is a true and correct copy of Form 8-K, Current Report
13 Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934, filed by Defendant dated 14 February 19, 2008. 15 32. Attached hereto as Exhibit TT is a true and correct copy of a document produced in this
16 litigation by Defendant, Bates numbered SRX-HOL00002757-2791. 17 33. Attached hereto as Exhibit UU is a true and correct copy of United States Patent No.
18 5,931,774, produced in this litigation by Defendant, Bates numbered SRX-HOL00002297-2307. 19 34. Attached hereto as Exhibit VV is a true and correct copy of a document produced in this
20 litigation by Defendant, Bates numbered SRX-HOL00002353-2358. 21 35. Attached hereto as Exhibit WW is a true and correct copy of a document produced in
22 this litigation by Defendant, Bates numbered SRX-HOL00002359-2370. 23 36. Attached hereto as Exhibit XX is a true and correct copy of a document produced in this
24 litigation by Defendant, Bates numbered SRX-HOL00006882-6898, marked Confidential-Outside 25 Counsel Only, and submitted under seal. 26 37. Attached hereto as Exhibit YY is a true and correct copy of a document produced in this
27 litigation by Defendant, Bates numbered SRX-HOL00003362-3379, marked Confidential-Outside 28 Counsel Only, and submitted under seal.
HOWREY LLP
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1
38.
Attached hereto as Exhibit ZZ is a true and correct copy of a document produced in this
2 litigation by Defendant, Bates numbered SRX-HOL00000406-430, marked Confidential-Outside 3 Counsel Only, and submitted under seal. 4 I declare under penalty of perjury that the foregoing is true and correct, and that this declaration
5 was executed on April 7, 2008, at East Palo Alto, California. 6 Dated: April 7, 2007 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
HOWREY LLP
HOWREY LLP
By:
/s/ Katharine L. Altemus
HOWREY LLP Attorneys for Plaintiffs Hologic, Inc., Cytyc Corporation, and Hologic LP
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Exhibit P
Case 5:08-cv-00133-RMW
(12)
111111111111111111111111111111111111111111111111111111111111111111111111111 US006413204Bl Document 75-2 Filed 04/07/2008 Page 2 of 12
(10)
(45)
United States Patent
Winkler et al.
Patent No.: US 6,413,204 Bl Date of Patent: *Jul. 2, 2002
(54)
INTERSTITIAL BRACHYTHERAPY APPARATUS AND METHOD FOR TREATMENT OF PROLIFERATIVE TISSUE DISEASES Inventors: Rance A. Winkler, Atlanta; Timothy J. Patrick; James Stubbs, both of Alpharetta, all of GA (US) Assignee: Proxima Therapeutics, Inc., Alpharetta, GA (US) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.c. 154(b) by 0 days. This patent is subject to a terminal disclaimer.
EP
GB
(75)
WO WO WO WO WO WO WO
0867200 2105201 9210932 9309724 9719723 9812979 9911325 9933515 9942163
9/1998 3/1983 7/1992 5/1993 6/1997 4/1998 3/1999 7/1999 9/1999
............ A6IN/1/06 ............ A6IN/5/02 ........... A6IB/17/36 ............ A6IN/5/oo ........... A6IB/19/oo
(73)
OTHER PUBLICATIONS A. Bex et al., A System for Focal Intracavitary Irradiation of Bladder Cancer with Remote Iridium-192 Afterloading, 21 Eur Urol 1992, 245-249 (1992). Ashpole, R.D. et al., "A New Technique of Brachtherapy for Malignant Gliomas with Caesium-137: A New Method Utilizing a Remote Afterloading System," Clinical Oncology, vol. 2, 333-7 (1990). Chun, M. et al., "Interstitial Iridium-192 Implantation for Malignant Brain Tumours. Part II: Clinical Experience," The British Journal of Radiology, vol. 62, 158-62 (1989). Garfield, J. et al., "Postoperative Intracavitary Chemotherapy of Malignant Gliomas," J. Neurosurg., vol. 39, 315-22 (Sep. 1973). (List continued on next page.)
( *)
(21) (22)
Appl. No.: 09/293,524 Filed: Apr. 15, 1999 Related U.S. Application Data
(63)
Continuation-in-part of application No. 08/900,021, filed on Jul. 4, 1997, now Pat. No. 5,913,813.
(51) (52) (58) (56)
Int. CI? U.S. Cl. Field of Search References Cited U.S. PATENT DOCUMENTS
3,324,847 3,872,856 4,417,576 4,706,652 4,754,745 4,763,642 A A A A A A 6/1967 3/1975 11/1983 11/1987 7/1988 8/1988 Zoumboulis .. Clayton Baran Horowitz Horowitz Horowitz
A61N 5/00 600/3 600/1-8
Primary Examiner-John P. Lacyk (74) Attorney, Agent, or Firm-Thomas J. Engellenner; Ronald E. Cahill; Nutter, McClennen & Fish, LLP
(57) ABSTRACT
128/1.2 128/1.2 128/207.15 128/1.2 128/1.2 128/1.2
(List continued on next page.) FOREIGN PATENT DOCUMENTS
An interstitial brachytherapy apparatus for delivering radioactive emissions to an internal body location includes a catheter body member having a proximal end and distal end, an inner spatial volume disposed proximate to the distal end of the catheter body member, an outer spatial volume defined by an expandable surface element disposed proximate to the distal end of the body member in a surrounding relation to the inner spatial volume, and a radiation source disposed in the inner spatial volume.
36 Claims, 3 Drawing Sheets
EP
0340881
11/1989
A6IN/5/1O
/0
\
/2
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U.S. PATENT DOCUMENTS
4,821,725 4,867,741 5,084,001 5,084,015 5,106,360 5,112,303 5,152,747 5,236,410 5,429,582 5,484,384 5,503,613 5,566,221 5,611,767 5,662,580 5,707,332 5,713,828 5,720,717 5,764,723 5,782,742 5,785,688 5,913,813 5,924,973 6,036,631 A A A A A A A A A A A A A A A A A A A A A A A 4/1989 9/1989 1/1992 1/1992 4/1992 5/1992 10/1992 8/1993 7/1995 1/1996 4/1996 10/1996 3/1997 9/1997 1/1998 2/1998 2/1998 6/1998 7/1998 7/1998 6/1999 7/1999 3/2000
6,059,812 A 128/420 A 604/10 600/3 604/96 600/2 604/49 604/93 600/12 600/2 600/3 600/3 378/145 600/2 600/3 600/3 600/7 604/21 378/65 600/3 604/141 600/3 600/3 600/3
* 5/2000 Clerc et al.
600/3
* *
Azam et al. Portnoy... Van't Hooft et al. Moriuchi Ishiwara et al. Pudenz et al. Olivier ...... Granov et al. Williams Fearnot Weinberger Smith et al. Williams Bradshaw et al. Weinberger Coniglione D'Andrea .. Weinberger et al. Crocker et al. Joshi et al. Williams et al. Wenberger McGrath et al.
OTHER PUBLICATIONS Gutin, P. et al., "Brachytherapy of Recurrent Malignant Brain Tumors With Removable High-Activity Iodine-125 Sources," J. Neurosurg., vol. 60, 61-8 (1984). Johannesen, T.B. et al., "Intracavity Fractionated Balloon Brachytherapy in Gilioblastoma," Aeta Neuroehir (Wien), vol. 141, 127-33 (1999). Leibel, S. et al., "The Integration of Interstitial Implantation Into the Preliminary Mangement of Patients With Malignant Gliomas: Results of a Phase II Northern California Oncology Group Trial," Am. J. Clin. Oneol. (CCl), vol. 10, No.2, p. 106 (1987).* Roberts, D. et al., "Interstitial Hyperthermia and Iridium Brachytherapy in Treamtnet of Malignant Glioma," J. Neurosurg., vol. 64,581-7 (1986).* Wu, A. et al., "Interstitial Iridium-192 Implantation for Malignant Brain Tumours, Part 1: Techniques of Dosimetry Planning," The British J ournal ofRadiology, vol. 62, 154-7 (1989).* * cited by examiner
u.s. Patent
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/2
FIG. 1
:~/4
16~
FIG. 2
34
36
44
28
FIG. 3
u.s.
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28
FIG.
32 26
1 I
4
36
30
FIG. 5
44 48
46
/2
FIG. 6
u.s. Patent
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FIG.7A
FIG.7B
FIG.7C
Absorbed Dose
A
B
c
52
-
---------~-~--~-----Icm 2cm
Surface of outer volume
DISTANCE FROM SURFACE OF OUTER VOLUME
FIG.7D
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distensible reservoir. Following surgical removal of a tumor, the surgeon introduces the balloon catheter into the surgically created pocket left following removal of the tumor. The balloon is then inflated by injecting a fluid having one or 5 more radio nuclides into the distensible reservoir via a lumen CROSS-REFERENCE TO RELATED in the catheter. APPLICATIONS The apparatus described in Williams solves some of the problems found when using radioactive seeds for interstitial This application is a continuation-in-part of U.S. patent brachytherapy, but leaves some problems unresolved. The application Ser. No. 08/900,021, filed Jul. 24, 1997, now U.S. Pat. No. 5,913,813 the contents of which are specifi- 10 absorbed dose rate at a target point exterior to a radioactive source is inversely proportional to the square of the distance cally incorporated herein by reference. between the radiation source and the target point. As a result, BACKGROUND OF THE INVENTION where the radioactive source has sufficient activity to deliver a prescribed dose, say 2 centimeters into the target tissue, the The invention relates generally to apparatus for use in treating proliferative tissue disorders, and more particularly 15 tissue directly adjacent the wall of the distensible reservoir, where the distance to the radioactive source is very small, to an apparatus for the treatment of such disorders in the may still be overly "hot" to the point where healthy tissue body by the application of radiation. necrosis may result. In general, the amount of radiation Malignant tumors are often treated by surgical resection desired by the physician is a certain minimum amount that of the tumor to remove as much of the tumor as possible. 20 is delivered to a region up to about two centimeters away Infiltration of the tumor cells into normal tissue surrounding from the wall of the excised tumor. It is desirable to keep the the tumor, however, can limit the therapeutic value of radiation that is delivered to the tissue in the target treatment surgical resection because the infiltration can be difficult or region within a narrow absorbed dose range to prevent impossible to treat surgically. Radiation therapy can be used over-exposure to tissue at or near the reservoir wall, while to supplement surgical resection by targeting the residual 25 still delivering the minimum prescribed dose at the maxitumor margin after resection, with the goal of reducing its mum prescribed distance from the reservoir wall. size or stabilizing it. Radiation therapy can be administered There is still a need for an instrument which can be used through one of several methods, or a combination of to deliver radiation from a radioactive source to target tissue methods, including external-beam radiation, stereotactic within the human body with a desired intensity and at a radiosurgery, and permanent or temporary interstitial brachytherapy. The term "brachytherapy," as used herein, 30 predetermined distance from the radiation source without over-exposure of body tissues disposed between the radiarefers to radiation therapy delivered by a spatially confined tion source and the target. radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. Owing to the SUMMARY OF THE INVENTION proximity of the radiation source, brachytherapy offers the 35 advantage of delivering a more localized dose to the target The present invention solves the problems described tissue region. above by providing an interstitial brachytherapy apparatus For example, brachytherapy is performed by implanting for delivering radioactive emissions to an internal body radiation sources directly into the tissue to be treated. location. The apparatus includes a catheter body member Brachytherapy is most appropriate where 1) malignant 40 having a proximal end and distal end, an inner spatial tumor regrowth occurs locally, within 2 or 3 em of the volume disposed proximate to the distal end of the catheter original boundary of the primary tumor site; 2) radiation body member, an outer spatial volume defined by an expandtherapy is a proven treatment for controlling the growth of able surface element disposed proximate to the distal end of the malignant tumor; and 3) there is a radiation dosethe body member in a surrounding relation to the inner response relationship for the malignant tumor, but the dose 45 spatial volume, and a radiation source disposed in the inner that can be given safely with conventional external beam spatial volume. The inner and outer spatial volumes are radiotherapy is limited by the tolerance or normal tissue. In configured to provide an absorbed dose within a predeterbrachytherapy, radiation doses are highest in close proximity mined range throughout a target tissue. The target tissue is to the radiotherapeutic source, providing a high tumor dose located between the outer spatial volume expandable surface while sparing surrounding normal tissue. Interstitial brachy- 50 and a minimum distance outward from the outer spatial therapy is useful for treating malignant brain and breast volume expandable surface. The predetermined dose range tumors, among others. is defined as being between a minimum prescribed absorbed dose for delivering therapeutic effects to tissue that may Interstitial brachytherapy is traditionally carried out using include cancer cells, and a maximum prescribed absorbed radioactive seeds such as 1251 seeds. These seeds, however, produce inhomogeneous dose distributions. In order to 55 dose above which healthy tissue necrosis may result. achieve a minimum prescribed dosage throughout a target In different embodiments, the inner spatial volume can be region of tissue, high activity seeds must be used, resulting defined by a distensible polymeric wall containing radioacin very high doses being delivered in some regions in tive source material which can be a fluid material, by a solid proximity to the seed or seeds which can cause radionecrosis radioactive source, or by a region containing a plurality of in healthy tissue. 60 solid radioactive sources. The outer spatial volume is Williams U.S. Pat. No. 5,429,582, entitled "Tumor defined by an expandable surface element that may be, for example, an inflatable polymeric wall or an expandable Treatment," describes a method and apparatus for treating cage. The expandable surface element can cause tissue to tissue surrounding a surgically excised tumor with radioacconform to its intended shape, and preferably, the apparatus tive emissions to kill any cancer cells that may be present in the tissue surrounding the excised tumor. In order to imp le- 65 creates absorbed isodose profiles in the target tissue that are substantially similar in shape to the expandable surface ment the radioactive emissions, Williams provides a catheter element in substantially three dimensions. having an inflatable balloon at its distal end that defines a INTERSTITIAL BRACHYTHERAPY APPARATUS AND METHOD FOR TREATMENT OF PROLIFERATIVE TISSUE DISEASES
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The invention also provides a method for treating a tion resistant polymer, such as silas tic rubbers, polyurethanes, polyethylene, polypropylene, polyester, or proliferating tissue disease using interstitial brachytherapy PVc. at an internal body location. The method includes surgically The embodiment of FIG. 1 includes inner and outer creating access to the proliferating tissue within a patient and surgically resecting at least a portion of the proliferating 5 spatial volumes 30 and 34, one inside the other. The outer spatial volume 34, being the volume defined by the space tissue to create a resection cavity within body tissue. An between the inner spherical wall 32 and the outer spherical interstitial brachytherapy apparatus for delivering radioacwall 36, may be filled with air or, alternatively, a radiation tive emissions as described above is then provided and absorbing fluid, such as a contrast media used in angiograintra-operatively placed into the resection cavity. After a prescribed absorbed dose has been delivered to tissue sur- 10 phy. The inner volume 30 is then filled with a material containing a predetermined radionuclide, for example, rounding the apparatus, the apparatus is removed. The 1-125, 1-131, Yb-169 or other source of radiation, such as radioactive source material may be placed into the interstiradio nuclides that emit photons, beta particles, gamma tial brachytherapy apparatus after the apparatus is placed in radiation, or other therapeutic rays. The radioactive material the resection cavity, and may be removed before the appacontained within the inner chamber 32 can be a fluid made ratus is removed. The method has particular applications to 15 from any solution ofradionuclide(s), e.g., a solution ofI-125 brain and breast cancers. or 1-131. A radioactive fluid can also be produced using a slurry of a suitable fluid containing small particles of solid DESCRIPTION OF THE DRAWINGS radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel. One radioactive The foregoing features, objects and advantages of the invention will become apparent to those skilled in the art 20 material useful in the invention is Iotrex?", a sterile single use, non-pyrogenic solution containing sodium 3-C 2 51)iodofrom the following detailed description of a preferred 4-hydroxybenzenesulfonate C 2 51-HBS), available from embodiment, especially when considered in conjunction Proxima Therapuetics, Inc. of Alpharetta, Ga. with the accompanying drawings in which: As an alternative method of providing radioactive source FIG. 1 is a side view of an interstitial brachytherapy 25 material, such material may be coated on, chemically apparatus of the invention for delivering radioactive emisbonded to, or copolymerized with the material forming inner sions to body tissue; spherical wall 32. FIG. 2 is a cross-sectional view taken along the line 2-2 Where the radioactive source material is provided as a in FIG. 1; fluid or gel within inner spherical wall 32, it may be FIG. 3 is an additional embodiment of an interstitial 30 desirable to provide a solid outer spherical wall 36. Should inner spherical wall 32 rupture, the radioactive source matebrachytherapy apparatus of the invention having a solid rial will be retained within outer spherical wall 36 and will radiation source; not leak into the patient. For further safety, the burst strength FIG. 4 is an additional embodiment of an interstitial of inner spherical wall 32 may be designed so as to be lower brachytherapy apparatus of the invention having a radiation 35 than that of outer spherical wall 36. In this way, inner source comprising a plurality of solid radiation particles; spherical wall 32 will rupture under stress first, releasing its FIG. 5 depicts a further embodiment of the invention contents into the larger combined space of the inner and wherein the inner and outer spatial volumes of the interstitial outer volumes 30, 34 and releasing any pressure built up brachytherapy apparatus are non-spherical; within the inner spherical wall 32 and reducing the risk that FIG. 6 illustrates an interstitial brachytherapy apparatus 40 radioactive material will spill into the patient. In the event of of the invention having an expandable outer spatial volume such a rupture, radioactive fluid could be drained from the surface; and apparatus through port 24 by way of lumen 14, and also from FIGS. 7A-D illustrate the absorbed dose versus distance port 26 by way of lumen 16. into target tissue for several interstitial brachytherapy appaIn a further embodiment, illustrated in FIG. 3, instead of ratus configurations. 45 having the inner spatial volume 30 defined by a generally spherical polymeric film wall as at 32, the catheter body DESCRIPTION OF THE PREFERRED member 12 may have a solid spherical radiation emitting EMBODIMENT material 44 as the inner spatial volume 30. For example, A surgical instrument 10 for providing radiation treatment radioactive micro spheres of the type available from the 3M to proliferative tissue in a living patient is illustrated in FIG. 50 Company of St. Paul, Minn., may be used. This radioactive 1. Surgical instrument 10 includes a tubular body member source can either be preloaded into the catheter at the time 12 having first and second lumens 14 and 16 (FIG. 2) of manufacture or loaded into the device after it has been extending from proximal ports 18 and 20 in a molded plastic implanted into the space formerly occupied by the excised hub 22 to inflation ports 24 and 26 formed through the side tumor. The solid radiation emitting material 44 can be wall of the tube 12 and intersecting with the lumens 14 and 55 inserted through catheter 12 on a wire 46, for example, using 16, respectively. an afterloader (not shown). Such a solid radioactive core Affixed to the tubular body 12 proximate the distal end 28 configuration offers an advantage in that it allows a wider range of radionuclides than if one is limited to liquids. Solid thereof is an inner spatial volume 30 which may be defined radio nuclides that could be used with the delivery device of by a generally spherical polymeric film wall 32. The interior of the inner volume 30 is in fluid communication with the 60 the present invention are currently generally available as inflation port 26. Surrounding inner spatial volume 30 is an brachytherapy radiation sources. In this embodiment solid outer spatial volume 34 defined by an outer polymeric film spherical inner spatial volume 30 is surrounded by outer wall 36 that is appropriately spaced from the wall 32 of the spherical wall 36, defining outer spatial volume 34 between inner spatial volume 30 when the two volumes are inflated the outer spherical wall 36 and the inner spatial volume 30 or otherwise supported. Outer volume 34 encompasses 65 with the outer spatial volume 34 occupied by a radioactive inflation port 24. With no limitation intended, the distensible ray absorbent material, such as air, water or a contrast polymeric film walls may comprise a biocompatible, radiamaterial.
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In a further embodiment, illustrated in FIG. 4, inner prescribed dose within target tissue while avoiding necrosis spatial volume 30, instead of comprising a single solid inducing radiation "hot spots" in tissue proximate to the sphere, may comprise a plurality of radiation emitting parapparatus. FIG. 7A illustrates an interstitial brachytherapy ticles 44 strategically placed within the inner spatial volume apparatus (device A) such as those employed in U.S. Pat. 30 so as to radiate in all directions with a substantially equal 5 No. 5,429,582, having a single spatial volume 50 filled with intensity. This plurality of radiation emitting particles 44 can a radioactive material in solution. FIG. 7B illustrates an be mounted on the distal ends of a plurality of wires 46 that interstitial brachytherapy apparatus (device B) of the invention having a first, inner spatial volume 30 filled with a are routed through the catheter body 12 and exit a plurality radioactive material in solution and defined by membrane of ports formed through the wall of the catheter body and reaching the lumen. This arrangement allows the exact 10 32, and a second, outer spatial volume 34 defined by membrane 36 that is substantially evenly spaced apart from positioning of the individual radiation sources 44 to be membrane 32 in substantially three dimensions. FIG. 7C positioned so as to generate a desired resultant profile. illustrates an additional interstitial brachytherapy apparatus As illustrated in FIG. 5, it is not essential to the invention (device C) of the invention having a solid, spherical radiathat the volumes 30 and 34 have spherical walls, so long as the resultant dosing profile is consistent with the shape of the 15 tion source 44 as the inner spatial volume and a spherical outer spatial volume 34 defined by membrane 36. outer volume 34. That is, the absorbed dose within the target Each of the devices illustrated in FIGS. 7A-C can be tissue at points equidistant from the surface 36 of the outer configured to deliver a substantially uniform dose at a given spatial volume 34 should be substantially uniform in subdistance into the target tissue from the surface of the outer stantially every direction. Put another way, the three dimensional isodose profiles generated by the radiation source 20 spatial volume 34 (or from single spatial volume 50 for device A) and to deliver a minimum prescribed dose within should be substantially similar in shape to the outer spatial a given prescribed depth range into the tissue from the volume 34. Where the inner and outer spatial volumes are surface of the outer spatial volume 34. However, the differcreated by inflatable membranes and one of the volumes ent devices provide very different dose profiles as a function contains a fluid radiation source, this can be achieved by ensuring that the spacing between the wall of the inner 25 of distance from the surface of the outer volume as illustrated in FIG. 7D. FIG. 7D plots the absorbed dose at a given volume and the wall of the outer volume remain generally distance into the target tissue from the surface of the outer constant. In either the concentric spherical embodiment of spatial volume 34 for each of the devices A, B, and C. FIG. 1 or the non-spherical configuration of FIG. 5, this result can be achieved by careful placement of precision Each device can deliver a minimum prescribed dose 52 at blown or molded polymer partitions or by using compress- 30 a given distance from the surface of the outer spatial volume. ible foams or mechanical spacers in the form of webs joining For example, device A can readily be configured to provide the inner wall 32 to the outer wall 36. The desired isodose a dose in a therapeutic range, say between 40 to 60 Gray, at profiles conforming to the shape of the outer spatial volume a distance between 0.5 and 1.0 em from the outer spatial 34 can also be obtained, for example, by strategic placement volume for an outer spatial volume having a diameter of 4.0 of a plurality of radioactive particle sources within the inner 35 em and being in contact with the resection cavity wall. In a spatial volume 30. Where the apparatus of the invention is typical embodiment, the radioactive source material ranges deployed in soft tissue, it may also be important for the from approximately 150 to 450 mCi in activity and encomsurface 36 of the outer spatial volume 34 to be sufficiently passes most of the target treatment area with a 0.4 to 0.6 firm so as to force the target tissue to take on the shape of Gray/hour isodose contour. At this treatment rate, treatment the surface 36 so that the desired relationship between the 40 may be completed in approximately 3 to 7 days, or more isodose profiles and the target tissue is achieved. commonly, in approximately 3 to 5 days. When used in an interstitial application, the surface of the In order to reach the minimum prescribed dosage at this outer spatial volume 34 must establish a relationship distance, however, device A must provide a dose proximate between the inner spatial volume 30 and the target tissue so to the surface of the outer spatial volume that is substantially as to achieve the aforementioned isodose profile, however, 45 larger than the minimum prescribed dose. For the 4.0 em the surface of the outer volume need not be a solid material. diameter outer spatial volume example, the absorbed dosage For example, as illustrated in FIG. 6, the surface of the outer would be approximately 131 Gray at the outer spatial volume 34 could be an expandable cage 48 formed from a volume surface. Ideally, radiation therapy should make use shape memory metal, such as nitinol, or a suitable plastic, the inherent difference in radiosensitivity between the tumor such as an expandable polyethylene cage. Such a cage can 50 and the adjacent normal tissues to destroy cancerous tissue be formed in the desired shape to conform to a particular while causing minimal disruption to surrounding normal isodose profile, then be contracted for delivery to the target tissues. At high doses of radiation, however, the percentage site in vivo, then expanded to cause the tissue surrounding of exposed cells that survive treatment decreases with firstthe surgically resected region to take the appropriate shape. order kinetics in proportion to increasing radiation dose. The size of the outer spatial volume 34 generally will 55 With increasing cell death comes increasing risk of necrosis correspond approximately to the amount of tissue resected, or tissue death in healthy tissue that is treated with a high or be slightly larger, allowing the expandable surface of the dose of radiation. Accordingly, it is desirable to keep the outer spatial volume to urge tissue on the surface of the maximum radiation dose delivered by the brachytherapy resected region into the appropriate shape to promote an apparatus as low as possible while still delivering the desired even dose distribution around the outer spatial volume in the 60 therapeutic dose to the desired range of tissue. target tissue. In typical applications, the outer spatial volume Comparing the plots A, B, and C, the absorbed dose has a diameter of approximately 2 to 4 centimeters. In these profile in the space between the 2 em site and the surface of same applications, where the radiation source is provided as the outer spatial volume for the devices of the invention is a fluid within an inner balloon, the inner balloon generally maintained in a much narrower range, preventing overhas a diameter of approximately 0.5 to 3 centimeters. 65 treatment of body tissue at or close to the surface of the outer FIGS. 7A-D illustrate the ability of an interstitial brachyvolume of the device. Because devices Band C provide an outer spatial volume 34 between the radioactive source and therapy apparatus of the invention to deliver a minimum
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delivered, typically for approximately a week or less. The radiation source is then retrieved and the catheter is removed. The radiation treatment may end upon removal of the brachytherapy apparatus, or the brachytherapy may be supplemented by further doses of radiation supplied externally. It will be understood that the foregoing is only illustrative of the principles of the invention, and that various modifications can be made by those skilled in the art without departing from the scope and spirit of the invention. All references cited herein are expressly incorporated by reference in their entirety. What is claimed is: 1. An interstitial brachytherapy apparatus for delivering radioactive emissions to an internal body location comprising: (a) a catheter body member having a proximal end and distal end; (b) an inner spatial volume disposed proximate to the distal end of the catheter body member; (c) an outer spatial volume defined by an expandable surface element disposed proximate to the distal end of the body member in a surrounding relation to the inner spatial volume; and (d) a radiation source disposed in the inner spatial volume and generating a three-dimensional isodose profile that is substantially similar in shape to the expandable surface element. 2. The apparatus of claim 1, wherein the inner and outer spatial volumes are configured to provide a minimum prescribed absorbed dose for delivering therapeutic effects to a target tissue, the target tissue being defined between the outer spatial volume expandable surface and a minimum distance outward from the outer spatial volume expandable surface, the apparatus providing a controlled dose at the outer spatial volume expandable surface to reduce or prevent necrosis in healthy tissue proximate to the expandable surface. 3. The apparatus of claim 2, wherein a predetermined spacing is provided between said inner spatial volume and the expandable surface element. 4. The apparatus of claim 3, wherein the expandable surface element is adapted to contact tissue surrounding a resected cavity and adapted to conform the tissue to the desired shape of the expandable surface element. 5. The apparatus of claim 2, wherein the minimum prescribed absorbed dose is 40 Gray at a distance of at least one centimeter from the expandable surface element. 6. The apparatus of claim 5, wherein the dose rate in at least a portion of the target tissue is between about 0.4 and 0.6 Gray/hour. 7. The apparatus of claim 5, wherein the maximum absorbed dose delivered to the target tissue is less than 100 Gray. 8. The apparatus of claim 2, wherein the outer spatial volume has a diameter between about two and four centimeters. 9. The apparatus of claim 2, wherein the inner spatial volume is an inner closed, distensible chamber defined by a further radiation transparent wall. 10. The apparatus of claim 9, wherein the radioactive source is in a fluid form. 11. The apparatus of claim 10, wherein the expandable surface element is a solid distensible surface and the outer spatial volume is a closed, distensible chamber and the expandable surface element is a radiation transparent wall.
the target tissue, these devices can use hotter radiation sources to reach the minimum prescribed dosage, but take advantage of the distance between the radioactive source and the target tissue provided by the outer spatial volume 34 to reduce or eliminate hot spots in the target tissue. Returning to the 4.0 em diameter outer spatial volume example, if the radiation source is contained within an inner spatial volume, say a solid radioactive sphere such as device C, the absorbed dose profile becomes much different. If the radiation source is configured to provide the same 60 Gray dose at 0.5 em into the target tissue, the absorbed dose at the outer spatial volume surface is only 94 Gray-a significant decrease from the 131 Gray dose for a type A device. In addition, the treatment range for the type C device will be extended under these circumstance as compared to the type A device, delivering a 40 Gray dose beyond 1.0 em into the target tissue and delivering approximately double the dose at 3.0 em into the target tissue. In one embodiment, the inner and outer spatial volumes are configured to control the absorbed dose at the outer spatial volume surface so that the absorbed dose is no greater than about 100 Gray while providing a therapeutic absorbed dose into the target tissue at the desired range. The capability of the apparatus of the invention to deliver absorbed doses deeper into the target tissue than prior interstitial brachytherapy devices while controlling the dose in proximity to the apparatus to reduce or eliminate the risk of healthy tissue necrosis allows for the use of brachytherapy in a greater number of cases. The interstitial brachytherapy apparatus of the invention can be used in the treatment of a variety of malignant tumors, and is especially useful for in the treatment of brain and breast tumors. Many breast cancer patients are candidates for breast conservation surgery, also known as lumpectomy, a procedure that is generally performed on early stage, smaller tumors. Breast conservation surgery is typically followed by postoperative radiation therapy. Studies report that 80% of breast cancer recurrences after conservation surgery occur near the original tumor site, strongly suggesting that a tumor bed "boost" of local radiation to administer a strong direct dose may be effective in killing any remaining cancer and preventing recurrence at the original site. Numerous studies and clinical trials have established equivalence of survival for appropriate patients treated with conservation surgery plus radiation therapy compared to mastectomy. Surgery and radiation therapy are the standard treatments for malignant solid brain tumors. The goal of surgery is to remove as much of the tumor as possible without damaging vital brain tissue. The ability to remove the entire malignant tumor is limited by its tendency to infiltrate adjacent normal tissue. Partial removal reduces the amount of tumor to be treated by radiation therapy and, under some circumstances, helps to relieve symptoms by reducing pressure on the brain. Amethod according to the invention for treating these and other malignancies begins by surgical resection of a tumor site to remove at least a portion of the cancerous tumor and create a resection cavity. Following tumor resection, but prior to closing the surgical site, the surgeon intraoperatively places an interstitial brachytherapy catheter apparatus, having an inner spatial volume and an outer spatial volume as described above but without having the radioactive source material loaded, into the tumor resection cavity. Once the patient has sufficiently recovered from the surgery, the interstitial brachytherapy catheter is loaded with a radiation source. The radioactive source dwells in the catheter until the prescribed dose of radiotherapy is
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12. The apparatus of claim 11, wherein a burst strength of the distensible chamber defining the outer spatial volume is greater than a burst strength of the chamber defining the inner spatial volume. 13. The apparatus of claim 1, wherein the expandable surface element is an expandable cage. 14. The apparatus of claim 13, wherein the expandable cage comprises a shape memory material. 15. The apparatus of claim 14, wherein the expandable cage comprises nitinol. 16. The apparatus of claim 1, wherein the radiation source is a solid radiation source. 17. The apparatus of claim 1, wherein the radiation source is a plurality of solid radiation sources arranged to provide an isodose profile having a shape substantially similar to the shape of the outer spatial volume. 18. The apparatus of claim 2, wherein the prescribed absorbed dose is delivered to the target tissue in substantially three dimensions. 19. A method for treating a proliferating tissue disease using interstitial brachytherapy at an internal body location comprising: (a) surgically creating access to the proliferating tissue in a patient; (b) surgically resecting at least a portion of the proliferating tissue to create a resection cavity within body tissue; (c) providing an interstitial brachytherapy apparatus for delivering radioactive emissions comprising: (i) a catheter body member having a proximal end and distal end; (ii) an inner spatial volume disposed proximate to the distal end of the catheter body member; (iii) an outer spatial volume defined by an expandable surface element disposed proximate to the distal end of the body member in a surrounding relation to the inner spatial volume; and (iv) a radiation source disposed in the inner spatial volume and generating a three-dimensional isodose profile that is substantially similar in shape to the expandable surface element; (d) intraoperatively placing the interstitial brachytherapy apparatus into the resection cavity until a prescribed absorbed dose has been delivered to tissue surrounding the apparatus; and (e) removing the interstitial brachytherapy apparatus. 20. The method of claim 19, further including placing the radioactive source into the interstitial brachytherapy apparatus after the step of placing the apparatus into the tumor resection cavity. 21. The method of claim 19, further including removing the radioactive source from the interstitial brachytherapy apparatus before the step of removing the apparatus. 22. The method of claim 19, wherein the proliferating tissue is a patient's brain. 23. The method of claim 19, wherein the proliferating tissue is a patient's breast. 24. The method of claim 19, further including configuring the inner and outer spatial volumes to provide a minimum prescribed absorbed dose for delivering therapeutic effects to a target tissue, the target tissue being defined between the outer spatial volume expandable surface and a minimum distance outward from the outer spatial volume expandable surface, the apparatus providing a controlled dose at the outer spatial volume expandable surface to reduce or prevent necrosis in healthy tissue proximate to the expandable surface.
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25. The method of claim 24, further including providing a predetermined spacing between said inner spatial volume and the expandable surface element. 26. The method of claim 25, wherein the expandable surface element is adapted to contact tissue surrounding a resected cavity and adapted to conform the tissue to the desired shape of the expandable surface element. 27. The method of claim 24, wherein the minimum prescribed absorbed dose is 40 Gray at a distance of at least one centimeter from the expandable surface element. 28. The method of claim 27, wherein the dose rate in at least a portion of the target tissue is between about 0.4 and 0.6 Gray/hour. 29. The method of claim 27, wherein the maximum absorbed dose delivered to the target tissue is less than 100 Gray. 30. The method of claim 24, wherein the outer spatial volume has a diameter between about two and four centimeters. 31. The method of claim 24, wherein the step of configuring the inner and outer spatial volumes includes expanding the inner and outer spatial volumes. 32. A method for treating a proliferating tissue disease using interstitial brachytherapy at an internal body location comprising: (a) surgically creating access to the proliferating tissue in a patient; (b) surgically resecting at least a portion of the proliferating tissue to create a resection cavity within body tissue; (c) providing an interstitial brachytherapy apparatus for delivering radioactive emissions comprising: (i) a catheter body member having a proximal end and distal end; (ii) an inner spatial volume disposed proximate to the distal end of the catheter body member; (iii) an outer spatial volume defined by an expandable surface element disposed proximate to the distal end of the body member in a surrounding relation to the inner spatial volume; and (iv) a radiation source disposed in the inner spatial volume; (d) intraoperatively placing the interstitial brachytherapy apparatus into the resection cavity; (e) configuring the inner and outer spatial volumes to provide a minimum prescribed absorbed dose for delivering therapeutic effects to a target tissue, the target tissue being defined between the outer spatial volume expandable surface and a minimum distance outward from the outer spatial volume expandable surface, the apparatus providing a controlled dose at the outer spatial volume expandable surface to reduce or prevent necrosis in healthy tissue proximate to the expandable surface; and (t) removing the interstitial brachytherapy apparatus. 33. The method of claim 32, wherein the step of configuring the inner and outer spatial volumes includes expanding the inner and outer spatial volumes. 34. A method for treating a proliferating tissue disease using interstitial brachytherapy at an internal body location comprising: (a) surgically creating access to the proliferating tissue in a patient; (b) surgically resecting at least a portion of the proliferating tissue to create a resection cavity within body tissue;
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(c) providing an interstitial brachytherapy apparatus for 36. An interstitial brachytherapy apparatus for delivering delivering radioactive emissions comprising: radioactive emissions to an internal body location compris(i) a catheter body member having a proximal end and ing: distal end; (a) a catheter body member having a proximal end and (ii) an inner spatial volume disposed proximate to the 5 distal end; distal end of the catheter body member; (b) an inner spatial volume disposed proximate to the (iii) an outer spatial volume defined by an expandable distal end of the catheter body member; surface element disposed proximate to the distal end (c) an outer spatial volume defined by an expandable of the body member in a surrounding relation to the surface element disposed proximate to the distal end of 10 inner spatial volume; and the body member in a surrounding relation to the inner (iv) a radiation source disposed in the inner spatial spatial volume; and volume; (d) a radiation source disposed in the inner spatial vol(d) intraoperatively placing the interstitial brachytherapy ume; apparatus into the resection cavity; wherein the inner and outer spatial volumes are configured (e) adapting the expandable surface element to contact 15 to provide a minimum prescribed absorbed dose for delivtissue surrounding the resection cavity to conform the ering therapeutic effects to a target tissue, the target tissue tissue to the desired shape of the expandable surface being defined between the outer spatial volume expandable element; surface and a minimum distance outward from the outer (f) delivering a prescribed absorbed dose to tissue sur- 20 spatial volume expandable surface, the apparatus providing rounding the apparatus; and a controlled dose at the outer spatial volume expandable (g) removing the interstitial brachytherapy apparatus. surface to reduce or prevent necrosis in healthy tissue 35. The method of claim 34, wherein the step of adapting proximate to the expandable surface. the expandable surface element includes expanding the outer surface volume. * * * * *
Case 5:08-cv-00133-RMW
Document 75-3
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Exhibit S
Case 5:08-cv-00133-RMW
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EXPRESS A!IAU:JNC L.YmI:.NOt'
Applicant(s) Application No. : 09/293,524 Filed Entitled April 15, 1999
!NTERSTITIAL
BRACJIYTl;IERAPY ApPARATUS AND'METHOD FOR TREATMENT OF PROLIFERATIVE TISSUB
Group Art Unit:
DISliASES
DocketNo.
101360-15 (fonnerly ONE-008)
. Certificate orMa/ling (37 e,F.R. 1.8(a»
August 17, 1999
Date of Signature and Mail Deposit
By:
Ronald E. Cahill
Re · No:38,403
Il'mQRMATIONDISCLOSURE STATEMENT Assistant Commissioner for Patents Washington. DC 20231
.DearSir:
Applicants hereby citefor therecord in this. application the enclosed documents listed on
the attached copy of PTa Form1449. The enclosed Information Disclosure Statement is
SRX-HOL00000314
Case 5:08-cv-00133-RMW
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Application NQ.: 091293,524 Filed: April 15, 1999 Group Art UnitNo.. 3736 :
being filed prior to themailing date of a first Office Action on the merits. Accordingly,
Applicants believe that no fee or certification is required.
The Assistant Commissioner is hereby authorized to charge payment of anyadditional
fees associated withthis communicanon or credit anyoverpayment to Deposit AccountNo. 141449.
Respectfully submitted,
NU'ITER, MCCLENNEN & FISH, LLP
Date: _.....£lo.!!lif>.''''''-''-'-'-~..<.August 17, 1999
_
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Ronald E. Cahill Reg. No.38,403
Attorney for Applicants
OneInternatioilal Place Boston, MA 02110-2699 Tel: (617)439-2782
Fax: (617)310-9782
763202.1
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SRX-HOL00000315
Case 5:08-cv-00133-RMW
Document 75-3
Filed 04/07/2008
Page 4 of 6
FormP'J'O-l449
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Case 5:08-cv-00133-RMW
Document 75-3
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315-22 (September 1973);
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SRX-HOL00000317
Case 5:08-cv-00133-RMW
Document 75-3
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Page 6 of 6
Form PTO-l449 (Il"!'. !l-83)
U.S.DEPARTMENT OF COMMERCE PATENTANDTRAJ>EMARX OFFICE
ATTY.OOClQn'NO: l013liO-IS (fOl1llOl'ly ONll-OOB)
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Case 5:08-cv-00133-RMW
Document 75-4
Filed 04/07/2008
Page 1 of 6
Exhibit T
Case 5:08-cv-00133-RMW
Clinical Oncology (1990) 2:333-337 © 1990 The Royal College of Radiologists
Document 75-4
Filed 04/07/2008
Page 2 of 6
Clinical Oncology
Original Article
A New Technique of Brachytherapy for Malignant Gliomas with Caesium137: A New Method Utilizing a Remote Afterloading System*
R. D. Ashpole1, H. Snyman1, J. A. Bullimore3, H. J. Appleby3, B. H. CumminsI and H. B. Coakham1'2
1 2 Department of Neurosurgery and Imperial Cancer Research Fund Paediatric and Neuro-Oncology Laboratory, Frenchay Hospital, Bristol and 3Bristol Radiotherapy and Oncology Centre, Bristol, UK
Abstract. Failure of conventional treatment to cure malignant gliomas has stimulated interest in various forms of brachytherapy. We describe a new method of using intracranial radiation utilizing a remotelycontrolled aflerloading system with a modified endotracheal tube as the applicator. The system used is the Selectron LDM/MDR (Nucleotron) which is a sophisticated machine widely available at radiotherapy centres and primarily used to treat gynaecological malignancies. It uses Caesium-137 in the form of spherical pellets in a linear source train within a sealed system. The applicator is implanted at the time of surgical resection. The inflated balloon stabilises the applicator and allows a suitable dose distribution at a distance from the source train to be achieved. Details of the implantation and radiation procedures as well as the dosimetry calculation are presented. The advantages are simplicity of use, the elimination of radiation risk to personnel and the combination of cytoreduction and applicator implantation in one surgical procedure. Keywords: Malignant glioma; Brachytherapy; Caesium-137; Remote afterloading
INTRODUCTION
Conventional treatment does not cure malignant gliomas. Therapeutic failure is wholly attributable to the inability of surgery and external beam radiotherapy to locally eradicate tumour cells, with nine out of ten recurrences occurring within the margins of the original tumour (Hochberg and Pruitt, 1980). Ionizing radiation is effective in prolonging survival (Salcman, 1980), with a linear correlation between radiation dose and length of survival (Walker et al., 1979), but the limited tolerance of normal brain has restricted the maximum permissible dose to about 55-60 Gy (Leibel and Sheline, 1987). This has stimulated interest in different ways of increasing therapeutic effectiveness (Gutin et al., 1984; Sewchand et al., 1984; Murray et al., 1986; Saleman et al., 1986) including adjuvant modalities such as hyperthermia and radiosensitizers (Nelson et al., 1986; Roberts et al., 1986). Caesium-137 has already been used to treat brain tumours in a stereotactically implanted and afterloaded applicator (Mantell et al., 1986). We now describe a new form of brachytherapy utilizing Caesium-137 in a remote afterloading system with a modified endotracheal tube as the applicator. It can be used to irradiate the tumour bed following surgical resection of the tumour. It may be used alone or in combination with external beam irradiation. The advantages are simplicity of use, elimination of radiation risk to personnel and the avoidance of salvage craniotomy for mass effect caused by late radionecrosis as experienced in brachytherapy methods using wire implants. Only one su
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