DETAILED ACTION
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 .
Claim Status
Claims 3, 6, 9-11, 13, 15, 17, 19-22, 25-27, 31-38, 40-76, and 78-91 have been cancelled; and claims 1, 12, and 14 have been amended, as requested in the amendment filed on 10/17/2025. Following the amendment, claims 1-2, 4-5, 7-8, 12, 14, 16, 18, 23-24, 28-30, 39, and 77 are pending in the instant application.
Claims 14, 29-30, 39, and 77 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and/or nonelected species in the Response filed 08/30/2024, there being no allowable generic or linking claim.
Claims 1-2, 4-5, 7-8, 12, 16, 18, 23-24, and 28 are under examination in the instant office action.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 1-2, 4-5, 7-8, 11-12, 16, 18, 23-24, 28, and 31 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Claim 1 has been amended to recite wherein the at least one of: anti-PD- 1 therapy, anti-PD-L1 therapy, or antiCTLA-4 therapy is an inhibitor antibody and has been further amended to recite wherein the BMP7 inhibitor comprises a BMP7 antagonist protein, a BMP7 neutralizing antibody, an inhibitory nucleic acid targeting BMP7 mRNA, or a BMP7 antagonist small molecule. In view of the amendment of claim 1, claims 1-2, 4-5, 7-8, 11-12, 16, 18, 23-24, 28, and 31 are now considered to comply with the written description requirement. As such, the rejection of claims 1-2, 4-5, 7-8, 11-12, 16, 18, 23-24, 28, and 31 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn.
Claims 1-2, 4-5, 7-8, 11-12, 16, 18, 23-24, 28, and 31 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement. Claim 1 has been amended to recite treating a breast cancer or a lung cancer in a patient. In view of the amendment of claim 1, claims 1-2, 4-5, 7-8, 11-12, 16, 18, 23-24, 28, and 31 are now considered to be enabled. As such, the rejection of claims 1-2, 4-5, 7-8, 11-12, 16, 18, 23-24, 28, and 31 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement, is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 11 and 31 were rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Routh et. al. (Cancer Res., July 2018, 78, 4753; previously cited on PTO-892; herein after referred to as "Routh"), non-patent literature by Bach et. al. (Molecular Therapy: Oncolytics, March 2018, 8, 1-13; previously cited on PTO-892; herein after referred to as "Bach"), and non-patent literature by Emens (Clin Cancer Res, February 2018, 24(3), 1-20; previously cited on PTO-892; herein after referred to as "Emens").
It is noted that claims 11 and 31 have been cancelled, rendering their rejection moot. As such, the rejection of claims 11 and 31 under 35 U.S.C. 103 in view of Routh, Bach, and Emens is withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1-2 and 12 stand as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Routh et. al. (Cancer Res., July 2018, 78, 4753; previously cited on PTO-892; herein after referred to as "Routh"), non-patent literature by Bach et. al. (Molecular Therapy: Oncolytics, March 2018, 8, 1-13; previously cited on PTO-892; herein after referred to as "Bach"), and non-patent literature by Emens (Clin Cancer Res, February 2018, 24(3), 1-20; previously cited on PTO-892; herein after referred to as "Emens").
Claims 4-5 stand as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Routh et. al. (Cancer Res., July 2018, 78, 4753; previously cited on PTO-892; herein after referred to as "Routh"), non-patent literature by Bach et. al. (Molecular Therapy: Oncolytics, March 2018, 8, 1-13; previously cited on PTO-892; herein after referred to as "Bach"), and non-patent literature by Emens (Clin Cancer Res, February 2018, 24(3), 1-20; previously cited on PTO-892; herein after referred to as "Emens"), as applied to claims 1-2 and 12 above, and in further view of US 2014/243403 A1 (previously cited on PTO-892; herein after referred to as "Singh").
Claims 7-8 stand as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Routh et. al. (Cancer Res., July 2018, 78, 4753; previously cited on PTO-892; herein after referred to as "Routh"), non-patent literature by Bach et. al. (Molecular Therapy: Oncolytics, March 2018, 8, 1-13; previously cited on PTO-892; herein after referred to as "Bach"), and non-patent literature by Emens (Clin Cancer Res, February 2018, 24(3), 1-20; previously cited on PTO-892; herein after referred to as "Emens"), as applied to claims 1-2 and 12 above, and in further view of US 2015/0118247 A1 (previously cited on PTO-892; herein after referred to as "Hotson") and non-patent literature published by Gollob et. al. (J. Immunol., 1999, 1652(8), 4472-4481; previously cited on PTO-892; herein after referred to as “Gollob”).
Claims 16 and 18 stand as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Routh et. al. (Cancer Res., July 2018, 78, 4753; previously cited on PTO-892; herein after referred to as "Routh"), non-patent literature by Bach et. al. (Molecular Therapy: Oncolytics, March 2018, 8, 1-13; previously cited on PTO-892; herein after referred to as "Bach"), and non-patent literature by Emens (Clin Cancer Res, February 2018, 24(3), 1-20; previously cited on PTO-892; herein after referred to as "Emens"), as applied to claims 1-2, 11-12, and 31 above, and in further view of US 2013/0071326 A1 (previously cited on PTO-892; herein after referred to as “Martinez”).
Claims 23-24 stand as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Routh et. al. (Cancer Res., July 2018, 78, 4753; previously cited on PTO-892; herein after referred to as "Routh"), non-patent literature by Bach et. al. (Molecular Therapy: Oncolytics, March 2018, 8, 1-13; previously cited on PTO-892; herein after referred to as "Bach"), and non-patent literature by Emens (Clin Cancer Res, February 2018, 24(3), 1-20; previously cited on PTO-892; herein after referred to as "Emens"), as applied to claims 1-2 and 12 above, and in further view of non-patent literature published by Gong et. al. (Journal for ImmunoTherapy of Cancer, June 2018, 6(46), 1-17; previously cited on PTO-892; herein after referred to as “Gong”).
Claim 28 stands as rejected under 35 U.S.C. 103 as being unpatentable non-patent literature by Routh et. al. (Cancer Res., July 2018, 78, 4753; previously cited on PTO-892; herein after referred to as "Routh"), non-patent literature by Bach et. al. (Molecular Therapy: Oncolytics, March 2018, 8, 1-13; previously cited on PTO-892; herein after referred to as "Bach"), and non-patent literature by Emens (Clin Cancer Res, February 2018, 24(3), 1-20; previously cited on PTO-892; herein after referred to as "Emens"), as applied to claims 1-2, 11-12, and 31 above, and in further view of non-patent literature published by Maione et. al. (Current Pharmaceutical Design, 2014, 20, 3894-3900; previously cited on PTO-892; herein after referred to as “Maione”).
Response to Arguments
On Pages 8-12 of Remarks, Applicant argues the following:
Claim 1 has been amended to recite a method for the treatment of a lung cancer or a breast cancer in a patient, and wherein the BMP7 inhibitor comprises a BMP7 antagonist protein, a BMP7 neutralizing antibody, an inhibitory nucleic acid targeting BMP7 mRNA, or a BMP7 antagonist small molecule. As such, claim 1 is now commensurate in scope with the synergistic results presented in the inventor declaration previously made of record, and the second inventor declaration submitted with the instant response.
The second inventor declaration provides additional statistical analysis, clearly demonstrating a synergistic effect for the claimed combination therapies. Exhibit A of the inventor declaration filed herewith demonstrates in two cancer models (4Tl and 344SQR) that individual therapies of αPDl and α344-5 do not show differences in tumor growth compared to the control, but the combination of αPDl and α344-5 shows statistically significant reductions in tumor growth when compared to individual therapies (represented by low p-values comparing individual and combination therapies). Exhibit B also demonstrates in a 4Tl model that tumor growth and survival for BMP7 knockdown and αPDl therapy are not significantly different from the control, but the combination of BMP7 knockdown and αPDl therapy show statistically significant reduction in tumor growth and improved survival compared to the control. The data in Exhibit B also demonstrates in a 344SQR model that αPDl and follistatin treatment alone have no statistical difference from control tumor growth and survival, but the combination of follistatin and αPDl therapy lead to significantly reduced tumor growth and improved survival. As such, the data presented show synergistic results in two cancer models (344SQR and 4Tl), and for three different types of BMP7 inhibition (shBMP7, follistatin, and α344-5).
Applicant’s arguments have been fully considered, but are deemed not persuasive.
With regard to Applicant’s arguments, the following are noted:
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
"[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992).
Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness. The patentability of an intermediate may be established by unexpected properties of an end product "when one of ordinary skill in the art would reasonably ascribe to a claimed intermediate the ‘contributing cause’ for such an unexpectedly superior activity or property." In re Magerlein, 602 F.2d 366, 373, 202 USPQ 473, 479 (CCPA 1979). "In order to establish that the claimed intermediate is a ‘contributing cause’ of the unexpectedly superior activity or property of an end product, an applicant must identify the cause of the unexpectedly superior activity or property (compared to the prior art) in the end product and establish a nexus for that cause between the intermediate and the end product." Id. at 479.
With regard to the second inventor declaration, it is noted that the data presented is still not considered to be commensurate in scope with the instant claims; the claims would require exact sequences of hairpins and names/sequences of the antibodies. Furthermore, it is noted that instant claim 1 is drawn to administering (i) at least one of anti-PD-1, ani-PD-L1, or anti-CTLA-4 inhibitory antibodies, whereas the instantly presented data is exclusively drawn to a specific anti-PD-1 antibody and (ii) a BMP7 antagonist protein, a BMP7 neutralizing antibody, an inhibitory nucleic acid targeting BMP7 mRNA, or a BMP7 antagonist small molecule, whereas the instantly presented data is exclusively drawn to BMP7 neutralizing antibody α344-5, shBMP7, or follistatin. The active agents claimed are not only those used in the method that made the data, and it is further noted that the exact combinations of active agents are not consistent across all data sets. Additionally, it is specifically noted that no clear evidence supporting a conclusion of synergism has been provided. While it is acknowledged that Applicant has provided some statistical analysis, none of the statistical analysis explicitly supports synergism, which requires effects beyond the additive effects of the individual components. Additionally, it is noted that with regard to Exhibit A, Applicant argues individual therapies of αPDl and α344-5 do not show differences in tumor growth compared to the control, but the combination of αPDl and α344-5 shows statistically significant reductions in tumor growth when compared to individual therapies, however it is specifically noted that at the last timepoint of 15 days in the 4T1 model the combination therapy versus α344-5 alone is not statistically significant. Similarly, in the 344SQR model, at the last timepoint of 15 days the combination therapy versus αPDl alone is not statistically significant. Furthermore, with regard to Exhibit B, it is noted that the only statistical comparisons provided are between the treatment conditions (BMP7 knockdown/inhibition only, PD1 treatment only, and the combination therapy) and the control (no treatment). No statistical analysis is provided between the treatment conditions. In view of the above, the argument regarding synergism associated with the instantly claimed combination therapy is not sufficiently supported. Furthermore, improved therapeutic effects of a combination therapy comprising administering an immune checkpoint inhibitor and a BMP7 inhibitor would be expected to have improved therapeutic effects based on the cited prior art.
It is noted that no specific arguments against the combination of cited references for the above-listed claim rejections under 35 U.S.C. 103 are provided. Furthermore, it is specifically noted that: (i) Routh implicates BMP7 in breast cancer immune evasion via reduction in CTLs; (ii) Bach implicates BMPs, including BMP7, in various cancers and that their signaling may be implicated in disease progression; BMPs may also have a role in drug resistance of cancer cells and employing BMP inhibitors may enhance efficiency of cancer treatment; and (iii) Emens teaches treating breast cancer with immune checkpoint inhibitors, and suggests their use in combination with other therapeutic modalities to promote response, improve response, and/or overcome resistance to immunotherapy (i.e., immune checkpoint inhibitors) as a monotherapy. Thus, it is maintained that it would have been obvious to one of ordinary skill in the art to develop a method for treating cancer wherein a BMP7 inhibitor is administered in combination with an anti-PD-L1 therapy because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. More specifically, both Routh implicates CTL levels in anti-tumor immunity and tumor immune evasion. Routh explicitly implicates BMP7 levels in CTL levels, wherein increased BMP7 expression (and thus activity) correlates with reduced CTL levels and increased immune evasion (see Abstract). Bach teaches (i) high expression of BMP7 is implicated in lung, breast, prostate cancer (Page 4-5); (ii) BMP7 signaling may be associated with clinical disease progression (Page 6, Column 2, Paragraph 1); (iii) it is suggested that overall BMPs and their involvements highly related to drug resistance of cancer cells and employing BMP family inhibitors may promisingly enhance efficiency of cancer treatment (Page 9, Column 1, Paragraph 1; emphasis added); and (iv) Bach identifies various BMP signaling inhibitors, including K02288, which is a BMP7 inhibitor (Page 9, Column 2, Paragraph 1). Emens teaches treating breast cancer with immune checkpoint inhibitors, and suggests their use in combination with other therapeutic modalities to promote response, improve response, and/or overcome resistance to immunotherapy (i.e., immune checkpoint inhibitors) as a monotherapy. Thus, the combination of cited references suggests that combining immune checkpoint inhibitors with an additional therapeutic modality would be expected to improve efficacy compared to monotherapy, as supported by Emens, wherein adding a BMP7 inhibitor specifically would be expected to achieve such a result by promoting CTL levels and therefore immune response to limit disease progression and enhance therapeutic efficacy, as supported by Routh and Bach. Additionally, Bach Table 2 indicates that high expression of BMP7 is implicated in lung, breast, and prostate cancer (Page 4-5) and it is suggested that BMP7 signaling may be associated with clinical disease progression (Page 6, Column 2, Paragraph 1). Furthermore, Routh provides a framework for discovering yet unappreciated mechanisms by which tumors evade the immune system, and presents first evidence that BMP7 expression by breast tumors can function to limit CTL trafficking (Abstract). Bach also identifies various BMP signaling inhibitors, including the protein follistatin (Page 2, Table 2) which is known in the art as a BMP7 antagonist, and K02288, which is a BMP7 inhibitor (Page 9, Column 2, Paragraph 1). Thus, improved therapeutic efficacy using BMP7 antagonist proteins and/or small molecules would be expected in cases of lung and/or breast cancer.
In view of the above, the inventor declaration under 37 CFR 1.132 filed 10/17/2025 and Applicant’s arguments are deemed insufficient to overcome the above-listed claim rejections under 35 U.S.C. 103.
Conclusion
Claims 1-2, 4-5, 7-8, 12, 14, 16, 18, 23-24, 28-30, 39, and 77 are pending. Claims 14, 29-30, 39, and 77 are withdrawn. Claims 1-2, 4-5, 7-8, 12, 16, 18, 23-24, and 28 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642