Ex Parte Kobayashi et al

Patent Trials and Appeals BoardJun 24, 2019

14868040 - (D) (P.T.A.B. Jun. 24, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/868,040 09/28/2015 36218 7590 06/26/2019 KLARQUIST SPARKMAN, LLP (OTT-NIH) 121 S.W. SALMON STREET SUITE#l600 PORTLAND, OR 97204-2988 FIRST NAMED INVENTOR Hisataka Kobayashi UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www .uspto.gov ATTORNEY DOCKET NO. CONFIRMATION NO. 4239-85538-12 7090 EXAMINER SANG,HONG ART UNIT PAPER NUMBER 1643 NOTIFICATION DATE DELIVERY MODE 06/26/2019 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docketing@klarquist.com nicole. salazar@klarquist.com AS CChair@klarquis t. com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte HISATAKA KOBAYASHI and PETER CHOYKE Appeal2018-008819 Application 14/868,040 Technology Center 1600 Before DEBORAH KATZ, TA WEN CHANG, and JOHN E. SCHNEIDER, Administrative Patent Judges. KATZ, Administrative Patent Judge. DECISION ON APPEAL Appeal2018-008819 Application 14/868,040 Appellants 1 seek our review, under 35 U.S.C. Â§ I34(a), of the Examiner's decision to reject claims 1-3, 8-11, and 16-18. 2 (Appeal Brief filed March 19, 2018 ("App. Br. 3").) We have jurisdiction under 35 U.S.C. Â§ 6(b ). An oral argument was held on June 5, 2019. We REVERSE. The Examiner entered three rejections, each under 35 U.S.C. Â§ 103 that Appellants' claims are obvious over the prior art, as provided in the table below. Claims Prior Art Citation in Answer 1-3, 8-11, and 16-17 Barrett3, Peng4, and Pages3-7 Frangioni5 1-3, 8-11, and 16-18 Gleysteen6, Peng, and Pages 7-10 Frangioni 1-3, 8-11, and 16-18 Barrett, Peng, Frangioni, Pages 10-12 and Bacus7 1 Appellants report that the real parties in interest are the United States of America, as represented by the Secretary of Dept. of Health and Human Services and licensee Aspyrian Therapeutics, Inc. (App. Br. 3.) 2 Claims 4 and 12 were canceled and claims 5-7, 13-15, 19, and 20 were withdrawn during prosecution. (See App. Br. 30-32.) 3 Barrett et al., "In Vivo Diagnosis of Epidermal Growth Factor Receptor Expression Using Molecular Imaging With a Cocktail of Optically Labeled Monoclonal Antibodies," 13 CLINICAL CANCER RES. 6639--48 (2007). 4 Peng et al., "Phthalocyanine dye as an extremely photostable and highly fluorescent near-infrared labeling reagent," 6097 PROC. OF SPIE 60970E-1- 69070E-I2 (2006). 5 Frangioni et al., US 2008/0073566 Al, published March 27, 2008. 6 Gleysteen et al., "Fluorescently Labeled Cetuxiumab to Evaluate Head and Neck Cancer Response to Treatment," 6 CANCER BIOLOGY & THERAPY el- e5 (2007). 7 Bacus, US 2001/0044124 Al, published November 22, 2001. 2 Appeal2018-008819 Application 14/868,040 The Examiner also maintained a rejection of claims 1-3, 8-11, and 16-18 on the grounds of obviousness-type double-patenting over claims 124 of copending application 15/318, 104 in view of Gleysteen. (See Examiner's Answer issued July 11, 2018 ("Ans.") 12-13.) Appellants do not present any arguments against this rejection. Because the claims of application 15/318, 104 are still undergoing examination, this rejection is provisional. Accordingly, we decline to render a decision on the rejection. Appellants' Specification is directed to methods and compositions for killing tumor cells with antibody-IR700 conjugates that bind to the surface of cells and have been irradiated with near infrared (NIR) light. (See Spec. 1: 13-16.) Appellants' claim 1 recites: A phototoxic pharmaceutical composition for treating a tumor expressing HERi, comprising: a phototoxic conjugate comprising an IR700 molecule conjugated to an antibody that binds HERI; and a pharmaceutical carrier, wherein the phototoxic conjugate exhibits phototoxicity to kill tumor cells expressing Herl. (App. Br. 30.) Appellants' claim 8 recites: A combination, comprising: a first pharmaceutical composition comprising a phototoxic conjugate comprising an IR 700 molecule conjugated to an antibody that binds HERi, wherein the phototoxic conjugate exhibits phototoxicity to kill tumor cells expressing HERI; and a second pharmaceutical composition comprising an additional therapeutic agent. (App. Br. 30-31.) 3 Appeal2018-008819 Application 14/868,040 Findings of Fact 1. Barrett teaches Cy5.5 labeled cetuximab, which is an anti- HERI antibody, that can be used to detect tumor cells expressing HERi and HER2 in vitro and in vivo. (Barrett Abstract, 6640, 6641.) 2. The Examiner finds that buffer and water are pharmaceutical carriers. (See Ans. 4.) 3. Barrett does not teach the infrared ionophore IR700 conjugated to the binding fragment of cetuximab. (See Ans. 5.) 4. Peng teaches compositions of the near-infrared ionophore IRDyeâ„¢ 700DX ("IR700") that can be conjugated with biomolecules, including antibodies. (Peng Abstract; see Ans. 5.) 5. Peng teaches that IR700 was found to be 45 to 128 times more photostable than "current near-IR fluorophores ... " and about 27 times more photostable than tetramethylrhodamine, "one of the most photostable organic dyes." (Peng Abstract; see Ans. 5.) 6. Peng teaches that IR 700 has excellent water solubility, does not aggregate in high ionic strength buffer, has a large extinction coefficient and high fluorescent quantum yield. (See Peng Abstract.) 7. Peng teaches IR700 antibodies generate sensitive, highly specific detection with very low background in Western blot and cytoblot assays. (See Peng Abstract.) 8. Frangioni teaches a composition comprising a near infrared fluorophore and a targeting ligand, such as an antibody, that binds to a specific component on a cell. (See Frangioni ,r 9.) 9. Frangioni teaches that the fluorophore can be IR700. (See Frangioni ,r 28.) 4 Appeal2018-008819 Application 14/868,040 10. Frangioni teaches conjugating a near infrared fluorophore to the specific antibody 7El 1-C5.3, which binds to PSMA. (See Frangioni ,r 43.) 11. Frangioni does not teach a composition of Panitumumab, Trastuzumab, or J59I antibodies conjugated to IR700. 12. Gleysteen teaches using Cy5.5 labeled cetuximab for imaging head and neck cancers. (See Gleysteen Abstract and e2.) 13. Gleysteen does not teach IR700 labeled cetuximab or IR700 labeled antibinding fragment of cetuximab. (See Ans. 8.) 14. Bacus teaches using labeled antibody directed to a tumor marker to stain samples from a patient both before and after chemotherapy to determine the individual's response to the chemotherapy. (See Bacus ,r,r 17 and 23.) Analysis We agree with the Examiner that it was known before the time Appellants filed their application that the anti-HERi antibody cetuximab could be labeled with the near infrared fluorophore Cy5.5. (See Ans. 4 and 8, citing Barrett Abstract and Gleysteen e2; FFs 1 and 8) We also agree with the Examiner that it was known before the time Appellants filed their application that the near infrared fluorescence labeling reagent IR 700 could be conjugated to antibodies. (See Ans. 5, citing Peng Abstract and Frangioni ,r 28; FFs 4, 8, and 9.) We agree with the Examiner further that IR700 was characterized in the prior art as having several advantages, including being about 45 to 128 times more photostable than current near infrared fluorophores known at the time. (See Ans. 5, citing Peng Abstract; FF 5.) As the Examiner finds, IR700 was known to have excellent water solubility, a large extinction coefficient, high fluorescent quantum yield, and to not 5 Appeal2018-008819 Application 14/868,040 aggregate in high ionic strength buffer. (See Ans. 5, citing Peng Abstract; FF 6.) Furthermore, we agree with the Examiner's finding that Peng teaches IR700 antibodies generate sensitive, highly specific detection with very low background in Western blot and cytoblot assays. (See Ans. 5, citing Peng Abstract; FF 7.) The Examiner determines that ordinarily skilled artisans would have considered a composition of IR700 conjugated to an antibody that binds HERi, such as cetuximab, to be obvious because both Cy5.5 and IR700 were known to be useful in labeling antibodies. (See Ans. 6 and 9.) The Examiner reasons that the substitution of IR700 for Cy5.5 is merely the substitution of one known element for another known element. (See id.) The Examiner determines, further, that one of ordinary skill in the art would have had a reasonable expectation of success making any of these substitutions because Peng teaches how to conjugate IR700 molecules to an antibody. (See Ans. 6 and 9-10; see Peng 60970E-2.) According to the Examiner, one of ordinary skill would have had a reason to and would have been motivated to make this substitution because of the advantages of IR 700 over other near infrared fluorophores taught in Peng. (See Ans. 6 and 9-10.) Each of the Examiner's findings is supported by the record and we agree with the Examiner's reasoning. We disagree with Appellants' argument that the Examiner fails to identify all the elements of the claimed compositions in the prior art, specifically a phototoxic composition, comprising an IR700 molecule conjugated to an antibody that binds HERL (See App. Br. 6-7.) Appellants argue that the phototoxic nature of the claimed composition was not recognized in the prior art at the time, citing 6 Appeal2018-008819 Application 14/868,040 the declaration of inventors Hisataka Kobayashi, M.D., Ph.D. and Peter Choyke, M.D. ("Kobayashi and Choyke Deel.") in support. (See id. at 7.) Although the Examiner acknowledges that the phototoxic nature of the claimed composition was not recognized, we agree that the phototoxic property of the claimed composition does not further limit the scope of the claimed antibody-IR700 conjugate. (See Ans. 14--16.) Drs. Kobayashi's and Choyke' s testimony that they are not aware of any prior publication teaching use of an antibody-IR700 molecule to treat a tumor is not in dispute. (See Kobayashi and Choyke Deel., ,r 4.) Nevertheless, as the Examiner explains, the cetuximab-IR700 conjugates suggested by the combinations of the teachings of the cited prior art have the same structure as the claimed antibody-IR700 conjugates. (See Ans. 15.) Appellants' current claims recite a composition with this structure, not the use of the composition. The structural limitations recited in Appellants' claims are the IR700 molecule, an antibody that binds HERi, and a pharmaceutical carrier. "[T]he patentability of apparatus claims must be shown in the structure claimed and not merely upon a use, function, or result thereof." In re Gardiner, 171 F.2d 313, 315-16 (Fed. Cir. 1948). Regardless of Appellants' arguments that the Examiner improperly relied on inherency, the claim term "phototoxicity" does not change the nature of these structural elements. (See App. Br. 8-9.) For example, Appellants do not argue or cite to any evidence that for the claimed composition to be phototoxic the antibody and IR700 must be linked in a specific way or that only a subset of conjugates is phototoxic. Thus, the Examiner need not have provided prior 7 Appeal2018-008819 Application 14/868,040 art that teaches the claimed antibody-IR700 conjugate composition would be phototoxic for it to have been obvious. We are also not persuaded by Appellants' arguments that those of ordinary skill in the art would not have been motivated to combine the cited references. (See id. at 12-17.) Appellants argue that the unappreciated feature of phototoxicity "destroys the motivation to combine the cited references relied upon by the Examiner." (Id. at 13.) The Supreme Court teaches that "[ u ]nder the correct analysis, any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,420 (2007). Because the determination of a reason to combine the references is "at the time of [the] invention," we are not persuaded that an unrecognized property can negate what was known. The record supports the Examiner's determination that it was known that antibodies could be conjugated to fluorophores and that IR700 was known to offer advantages over other fluorophores. Thus, the record supports the Examiner's determination that those of ordinary skill would have had a reason to make cetuximab-IR700 fluorophores. KSR instructs that even though this reason is different from the reason Appellants had for conjugating IR 700 to antibodies, the claimed composition could still have been obvious. Despite the Examiner's citation of prior art teaching the structural components of the claimed composition and a reason to combine these teachings, we are persuaded that the Examiner erred in evaluating Appellants' evidence of secondary considerations, specifically unexpected results. (See App. Br. 18-22.) See In re Sullivan, 498 F.3d 1345, 1352 (Fed. 8 Appeal2018-008819 Application 14/868,040 Cir. 2007) ("Whether the composition would have been obvious cannot be determined without considering evidence attempting to rebut the prima facie case."). Appellants present persuasive evidence that the claimed composition is unexpectedly phototoxic against cancer cells displaying the antigen of the cognate antibody. Appellants present the testimony of Drs. Kobayashi and Choyke, that it was surprising that antibody-IR700 molecules effectively treat tumor cells, given that IR700 without an attached antibody is ineffective. (See Kobayashi and Choyke Deel., ,r,r 5 and 12.) Drs. Kobayashi and Choyke support their testimony with data, for example, Figure 6E of Appellants' Specification, which is reproduced below. ~ Pz.-1~ :)fi{! :.:') :\.". ~H) ~: ! ""#'" f\.'\~1~Â·:f~r~J x~c: :-.:':~ :/, :,o ptÂ·f F!G,6E Figure 6E is a graph of tumor volume as a function of time after injection under different treatments. As Drs. Kobayashi and Choyke explain, irradiated IR700 alone ("IR700 dye iv. PIT 30 J/cm2" in Fig. 6E) did not have any detectable effect on tumor growth over no treatment, but an irradiated conjugate of the anti-HERi antibody (Panitumamab) and IR700 ("Pan-IR700 300 Âµg iv, PIT 30 J/cm2" in Fig. 6E) resulted in significant tumor growth inhibition at 3, 7, 10, 14, and 17 days after treatment. (See id. 9 Appeal2018-008819 Application 14/868,040 ,r 9.) Drs. Kobayashi and Choyke testify further that the Pan-IR700 conjugate without irradiation also failed to reduce tumor volume. (See Kobayashi and Choyke Deel. ,r 9.) Drs. Kobayashi and Choyke also testified about Figure 6F of Appellants' Specification, which is reproduced below. No i.reutn;en! Â· - Pan )00 ;.1n iv, no PIT 1 .0~---Â·Â·Â·Â·Â· .. Â·:Â·Â·Â·tt--"-, ~,#,~ Pan-lR700 :'JOO Pli iv. no PIT ! ~- r:\ "'''"'' ~~') M.Ab Pl r ".'-0 .JJ::mÂ· j 2:0.5 :J (/J , , 1. ,,.. IR'7iv~ :v. p,r 30 JicmÂ·:Â· xr b : l ""?:'""' ;a~,:;~ 700 300 ,if} iv. Pi: ~.!) .Ji;:nfl ~i:.~J~ >.-~ } ~L1.C; C~ cLi r'.:---_J,. 10 20 30 40 Time after MAb injection {day) FIG. 6F :-,f . 50 Figure 6F is a graph of survival of mice as a function of time after injection under different treatments. As Drs. Kobayashi and Choyke explain, irradiated IR700 alone ("IR700 dye iv PIT 30 J/cm2" in Fig. 6F) did not increase the survival of mice, but irradiated Pan-IR 700 conjugate ("Pan- IR 700 300 Âµg iv, PIT 30 J/cm2" in Fig. 6F) resulted in a significant increase in survival time. (See id. ,r 10.) Drs. Kobayashi and Choyke testify further that other treatments (Pan-IR700 conjugate without irradiation, antibody alone, irradiation alone) failed to increase survival for comparison. (See id.) In addition to the testimony of Drs. Kobayashi and Choyke regarding Pan-IR700 compositions, Appellants present the testimony of Gary L. Griffiths, Ph.D., who is not a named inventor. (See App. Br. 20, citing Declaration Under 37 C.F.R. Â§ 1.132 of Gary L. Griffiths, Ph.D. ("Griffiths 10 Appeal2018-008819 Application 14/868,040 Deel.").) Dr. Griffiths testifies to the unexpected therapeutic value of the claimed compositions: Finally, the IR 700-MAb conjugates of the current invention do not require cellular internalization for their therapeutic effectiveness. This importance of this unexpected finding cannot be overemphasized due to the following general observations: MAbs are [in some quarters] considered ineffective due to their limited abilities to be internalized after binding. As such they may be considered by some as poor delivery vehicles for therapeutic drugs generally [ not just PDT agents] since drugs need to exert their therapeutic effects inside cells. Thus, despite their promise over 30 years, only limited numbers of approved agents have been approved clinically, and these use exceptionally toxic drugs (Teicher and Doroshow, New Engl., J. Med. (2012), 367:1847-1848, Exhibit F). Since the PIT of the current invention exerts its potent effects without need for cellular internalization of the long circulating IR 700- MAbs and is toxic only when cell-bound and exposed to near- infra red light, it represents a paradigm-shifting approach to MAb-directed cancer therapies not heretofore envisaged in the general or scientific literatures. (Griffiths Deel. ,r 19 (bracketed text present in original).) We understand from Dr. Griffith's testimony that the other HERi-binding antibody-IR700 conjugates as recited in Appellants' claims would have similarly unexpected results as Pan-IR700 because they would also be phototoxic without the need for cellular internalization. In light of the testimony of Drs. Kobayashi, Choyke, and Griffiths, we are persuaded that even if one of ordinary skill in the art would have had reason to combine the teachings of the prior art to make cetuximab-IR700, the phototoxic properties of the conjugate would have been unexpected. 11 Appeal2018-008819 Application 14/868,040 The Examiner's reasoning does not persuade us that the claimed composites are obvious regardless of these unexpected results. According to the Examiner, because antibody-IR700 conjugates are taught in Peng and Frangioni and there is no evidence that only anti-HERi antibody-IR700 conjugates are phototoxic, Appellants have not shown that the claimed conjugates demonstrate specifically unexpected results. (See Ans. 28-29.) In the Examiner's view, phototoxicity is an unrecognized property of any anti-tumor antibody-IR700 conjugate, and Appellants have not presented evidence that the phototoxicity of Appellants' specifically claimed conjugates (anti-HERi antibody-IR700) is unexpected compared to the conjugates taught in Peng and Frangioni. (See Ans. 29.) Thus, the Examiner does not consider Appellants' evidence of unexpected results to overcome the rejection for obviousness. (See id. at 29-30.) We disagree with the Examiner. Appellants claim compositions of IR700 conjugated to antibodies that bind HER-I only. Therefore, we evaluate only whether these conjugates produce unexpected results over the closest prior art. Neither Peng nor Frangioni, nor any other art cited by the Examiner, teaches these specific conjugates. The prior art teaches IR 700, but not that it is phototoxic. Indeed, none of the cited prior art teaches that any antibody-IR700 conjugate is phototoxic. Whether or not other antibody- IR700 conjugates would also be phototoxic does not negate that at the time of Appellants' filing, given the cited knowledge in the art, the phototoxic nature of the claimed composition would have been unexpected. When we consider Appellants' evidence of unexpected results along with the evidence of obviousness the Examiner finds in the prior art, we are persuaded that the claimed compositions would not have been obvious to 12 Appeal2018-008819 Application 14/868,040 those of ordinary skill in the art. Although the prior art cited teaches conjugating near infrared fluorophores, including IR700, to antibodies in general, none of the prior art teaches the specific conjugates claimed. Furthermore, although the prior art cited suggests that the claimed conjugates would be expected to be useful as tumor imaging agents, there is no suggestion from the cited prior art that the claimed compounds would be useful as phototoxic agents. Considered as a whole, the unexpected and different property of phototoxicity outweighs the suggestion in the art to combine the recited elements. See Honeywell Int 'l Inc. v. Mexichem Amanco Holding S.A. DEC. V., 865 F.3d 1348, 1355 (Fed. Cir. 2017) ("What is important regarding properties that may be inherent, but unknown, is whether they are unexpected. All properties of a composition are inherent in that composition, but unexpected properties may cause what may appear to be an obvious composition to be nonobvious. "). Conclusion Upon consideration of the record and for the reasons given, the rejections of claims 1-3, 8-11, and 16-18 as being obvious over the cited prior art are not sustained. Therefore, we reverse the decision of the Examiner. REVERSED 13