Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 19, 24-27, 65-71 and 75-79 are pending in the present application.
AMENDMENTS
Applicant's submission filed on 01/09/2026 has been entered.
Previous Claim Rejections - 35 USC § 112
Claims 51, 57, 65-66 and 72-76 were previously rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Applicant has canceled claims 51, 57 and 72-74 and traversed the rejection on the grounds claim 75 no longer recites “pathway”. See page 6 of Applicant’s remarks dated 01/09/2026.
The Examiner has considered the amendment and traversal fully but must disagree for the following reasons. While the rejection of claims 51, 57 and 72-74 is obviated by the cancelation of the claims 28-64 and 72-74, claims 65-66 are directed to previously elected subject matter which is now dependent upon a canceled claim. Although Applicant has indicated claims 65-66 as withdrawn in the amended claims dated 01/09/2026, the claims are directed to subject matter encompassed by Applicant’s previous election of invention and species, the claims have been previously examined and the claims will continue to be examined.
The previous rejection of claims 65-66 is maintained. The previous rejection of claims 51, 57 and 72-76 is withdrawn.
Previous Claim Rejections - 35 USC § 103
Claims 51, 57, 65-66 and 72-76 were previously rejected under 35 U.S.C. 103 as being unpatentable over Muraoka et al. (WO 2015/046498, with all citations from US PGPUB 2016/0228417 as an English translation) in view of Proia et al. (WO 2016/130502).
Applicant has traversed the previous rejection on the grounds Gantespib was known as an cytotoxic agent, one of ordinary skill in the art would not look to Muraoka given the toxicity for guidance regarding combining immunological agents, HSP inhibition irreversibly down regulated immunoactivity and the Examiner has cited no evidence that tone skilled in the art would combine an immunostimulatory agent with a cytotoxic agent.
The Examiner has considered the amendment and traversal fully but must disagree for the following reasons.
With regards to potential ganetespib as an alleged cytotoxic agent as well as adverse effects resulting from combination therapy, it is noted that an absolute predictability of success, where the combination of an HSP90 inhibitor such as TAS-116 and a PD-1 antibody such as nivolumab can be predicted to be 100% safe or effective, is not required to establish a case of obviousness. Conclusive proof of efficacy is not required to show a reasonable expectation of success. See MPEP 2143.02, Section I. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).
Muraoka discloses TAS-116 has a greater antitumor effect compared to ganetespib, providing the motivation to select alternative HSP90 inhibitors. Moreover, given the mortality rate of ganetespib, one of skill in the art would have been motivated to search for alternative HSP90 inhibitors. The search for alternative HSP90 inhibitors may have guided one of ordinary skill in the art to the compound and methods of Muraoka.
Regarding the data provided from Bae and from the present specification, it is noted that the features upon which Applicant relies (i.e. upregulation of immunostimulatory activity for Compound 1) are not recited in the rejected claims and, therefore, these features do not carry any weight in terms of an obviousness analysis. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See MPEP 716.02 (d) and MPEP 716.02 (e).
Applicant refers to alleged unexpected results; however, even if the results were considered unexpected, the results would not be commensurate in scope with the scope claims. Further, the results provided do not occur over the entire claimed range (a method for treating a tumor comprising administering 80 to 320 mg/body/day of Compound 1 on a schedule of 5 days on followed by 2 days off for 3 weeks and administering at least one immune checkpoint inhibitor once a cycle) of present claim 75.
Regarding the dosing and administration schedule limitations, Muraoka teaches a method for the treatment of a tumor comprising the administration of 5-28 mg/kg of body weight of Compound 1 in combination with 12.5-30 mg/kg of body weight of various antitumor agents, where Compound 1 was administered orally on days 1, 3, 5, 8, 10 and 12. See paragraphs 231, 235 and 243-244 in Examples 1-6, pages 14-26. Muraoka also discloses where the administration schedule of the antitumor agent of the invention is appropriately selected in the range in which each active ingredient exerts the antitumor effect, and each active ingredient is administered simultaneously or separately at an interval. The antitumor agent of the invention may be prepared in such a manner that respective active ingredients are separated into multiple dosage forms or are collectively prepared in one dosage form, on the basis of the administration forms or the administration schedules of the active ingredients. See paragraphs 216-217 of Muraoka. Proia discloses administration of 125 mg/kg HSP90 inhibitor, as Ganetespib, in combination with 200 µg of anti-PD-L1 antibody. Ganetespib was administered on days 8 and 15 while the antibody was administered on days 8, 12 and 15. See paragraph 58 on page 15 as well as Examples 2-6 on pages 16-18. Proia generally teaches administration of 2 mg/m2 to 260 mg/m2 of HSP90 inhibitor in combination with 100 mg/m2 to 200 mg/m2 of PD-1 inhibitor and that a treatment cycle can last between one and 6 weeks. See paragraphs 42-48 on pages 11-13.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05, Section II, subsection A.
As the combination of an HSP90 inhibitor and a PD-1 inhibitor is known in the art through Proia et al. and Muraoka et al. further teaches the compound of claim 75 exhibits a markedly superior antitumor effect and has a reduced side effect, there would be a reasonable expectation of success of safety and efficacy. Further, as both Muraoka and Proia provide dosing and scheduling guidance, it would have been obvious to one of skill in the skill to optimize the amount and administration schedule during routine experimentation.
Therefore, the previous rejection is maintained in an amended form based on Applicant’s amendment.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 65-66 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 65 recites the limitation "the method of claim 57" in line 1. There is insufficient antecedent basis for this limitation in the claim as claim 57 has been cancelled.
Claim 66, which is dependent upon claim 65, is similarly rejected.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 76 and 79 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 75 recites a method for treating a tumor, wherein the cycle is repeated for two to three weeks.
Claim 76, which is dependent upon claim 75, recites the method of claim 75 wherein the cycle is repeated. As claim 75 already recites the limitation of wherein the cycle is repeated, claim 76 is not further limiting.
Claim 79 recites The method of claim 75, wherein 3-ethyl-4- {3-isopropyl-4-(4-(1- methyl-1H-pyrazol-4-yl)-1H-imidazol-l-yl)-lH-pyrazolo[3,4-b]pyridin-1-yl} benzamide (TAS 116) is an immunostimulant. The limitation of TAS 116 as an immunostimulant is not a further limitation on claim 75 as the properties of a particular compound are inseparable from the structure of the same compound.
"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. See MPEP 2112.01(II).
It is presumed that TAS 116 acts as an immunostimulant in the method of claim 75 and claim 79 is not further limiting.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 65-66, 75-77 and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Muraoka et al. (WO 2015/046498, with all citations from US PGPUB 2016/0228417 as an English translation) in view of Proia et al. (WO 2016/130502).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Muraoka et al. teach the combination of the compound of present claim 75 with another anticancer drug such as docetaxel and paclitaxel. See paragraph 209, page 13 for the identification of the compound as Compound 1 and Examples 1-6, pages 14-26 of the US Muraoka et al. document. The compound reads on the claims where X1 and X2 are N, X3-X4 are CH, Y2 is C-R4, Y1 and Y3-Y4 are CH, R1 is substituted imidazole, R2 is alkyl having three carbon atoms, R3 is CONH2, and R4 is alkyl having two carbon atoms.
Muraoka teaches a method for the treatment of a tumor comprising the administration of 5-28 mg/kg of body weight of Compound 1 in combination with 12.5-30 mg/kg of body weight of various antitumor agents, where Compound 1 was administered orally on days 1, 3, 5, 8, 10 and 12. See paragraphs 231, 235 and 243-244 in Examples 1-6, pages 14-26. Muraoka also discloses where the administration schedule of the antitumor agent of the invention is appropriately selected in the range in which each active ingredient exerts the antitumor effect, and each active ingredient is administered simultaneously or separately at an interval. The antitumor agent of the invention may be prepared in such a manner that respective active ingredients are separated into multiple dosage forms or are collectively prepared in one dosage form, on the basis of the administration forms or the administration schedules of the active ingredients. See paragraphs 216-217 of Muraoka.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
Muraoka et al. do not teach where the additional compound is a PD-1 inhibitor such as nivolumab.
Finding of prima facie obviousness --- rationale and motivation (See
MPEP § 2142-2143)
Proia et al. teach the combination of an HSP90 inhibitor with the PD-1 inhibitor nivolumab for the treatment of tumors by administration of the HSP90 inhibitor ganetespib with an anti-PD-1 antibody. See Examples 1 and 2, pages 15-17. The PD-1 inhibitor nivolumab is preferred. See paragraph 5, page 2 and paragraph 45, page 12.
Proia discloses administration of 125 mg/kg HSP90 inhibitor, as Ganetespib, in combination with 200 µg of anti-PD-L1 antibody. Ganetespib was administered on days 8 and 15 while the antibody was administered on days 8, 12 and 15. See paragraph 58 on page 15 as well as Examples 2-6 on pages 16-18. Proia generally teaches administration of 2 mg/m2 to 260 mg/m2 of HSP90 inhibitor in combination with 100 mg/m2 to 200 mg/m2 of PD-1 inhibitor and that a treatment cycle can last between one and 6 weeks. See paragraphs 42-48 on pages 11-13.
The person of ordinary skill in the art would be motivated to combine the teachings of Muraoka et al. and Proia et al. to arrive at the instantly claimed invention as Muraoka et al. show that combining the compound of claim 75 with other cancer therapies can have a synergistic effect as shown in the Examples of Muraoka et al. As Proia et al. also teach that a synergistic effect is shown when another HSP90 inhibitor, ganetespib, is paired with the PD-1 inhibitor nivolumab, the person of ordinary skill would expect a similar effect if the additional therapy in Muraoka et al. was switched to nivolumab. Muraoka et al. teach that the effect was seen in other antitumor agents having different action mechanisms. See paragraph 13, page 1 of the US Muraoka et al. document. Since the mechanism of the additional anti-tumor agent of Muraoka et al. is not limited, a PD-1 inhibitor such as nivolumab would be a drop-in replacement and would be expected to have similar synergistic effects.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05, Section II, subsection A.
As the combination of an HSP90 inhibitor and a PD-1 inhibitor is known in the art through Proia et al. and Muraoka et al. further teaches the compound of claim 75 exhibits a markedly superior antitumor effect and has a reduced side effect, there would be a reasonable expectation of success of safety and efficacy. Further, as both Muraoka and Proia provide dosing and scheduling guidance, it would have been obvious to one of skill in the skill to optimize the amount and administration schedule during routine experimentation.
Regarding the limitation directed to where the treatment cycle is repeated, it would have been obvious to one of ordinary skill in the art to repeat or continue treatment for a tumor following the conclusion of an effective treatment cycle. There would be a reasonable expectation of success towards subsequent treatment cycles given the results of the first cycle.
Regarding claim 79, as Muraoka and Proia disclose the compound of present claim 75, the prior art teaches the instantly claimed properties as an immunostimulant.
"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. See MPEP 2112.01(II).
Double Patenting
Claims 65-66, 75-77 and 79 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-20 of copending Application No. 19/031,720 in view of Muraoka et al. (WO 2015/046498, with all citations from US PGPUB 2016/0228417 as an English translation) and Proia et al. (WO 2016/130502).
Claim 12 of the ‘720 application discloses a method for treating a tumor, comprising administering to a subject in need thereof an azabicyclo compound or a salt thereof and an immune checkpoint molecule regulator in combination, the azabicyclo compound being represented by the general formula (I).
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Claim 14 of the ‘720 application discloses wherein the azabicyclo compound is 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H- pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.
Claims 18-20 of the ‘720 application disclose wherein the immune checkpoint molecule regulator is a PD-1 pathway antagonist, further specified as an anti-PD-1 antibody, and where the anti-PD-1 antibody is selected from the group consisting of nivolumab and pembrolizumab.
The claims of the ‘720 application do not disclose or suggest where 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H- pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide is administered at a dosage of 80 to 320 mg/body/day on a schedule of 5 days on followed by 2 days off for 3 weeks or administering an anti- CTL-4 pathway antibody once every two to three weeks for nivolumab and every three weeks for anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies and anti- CTL-4 pathway antibodies.
As the ‘720 application discloses the compound of present claim 75 in a method for treating a tumor, in combination with an anti-PD-1 antibody, one of skill in the art would have been motivated to arrive at the present invention in view of the combination of Muraoka et al. and Proia et al. as referenced in the 103 rejection above. The rationale from the 103 rejection over claims 65-66, 75-77 and 79 in view of Muraoka et al. and Proia et al. is incorporated herein by reference.
Conclusion
Claims 19, 24-27, 65-71 and 75-79 are pending.
Claims 19, 24-27, 67-71 and 78 are withdrawn.
Claims 65-66, 75-77 and 79 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QUINCY A MCKOY whose telephone number is (703)756-4598. The examiner can normally be reached Monday - Thursday 8:00 - 6:00.
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/QUINCY A. MCKOY/
Patent Examiner, Art Unit 1626
/KAMAL A SAEED/Primary Examiner, Art Unit 1626
/JOSEPH K MCKANE/Supervisory Patent Examiner, Art Unit 1626