DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/19/2025 has been entered.
3. Claims 1, 12, 14-24 are pending.
4. Claims 12, 14-17, 21-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
5. Claims 1 and 18-20 are under examination as they read on the species of:
A. immunoconjugate as ADAM12 inhibitor and anti-VEGF antibody as the second anti-tumor compound;
B. a composition that does not further comprise an adjuvant or immune modulator;
C. a composition that does not further does not further comprise a DPP4 inhibitor.
6. 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.
7. Claims 1 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2006014903 (IDS) in view of US 20120065251 and Hurwitz et al (N Engl J Med . 2004 Jun 3;350(23):2335-42) or US 20080214576.
The `903 publication teaches anti-ADAM12 antibodies in combination with standard chemotherapeutic or radiation regimens (anti-tumor compound) to treat cancers (must be in a pharmaceutical composition). Anti-ADAM 12 antibodies can act to sensitize the cancer cells to chemotherapy or radiation, allowing for more efficient tumor killing. Alternatively, anti-ADAM12 antibodies can act in synergy with chemotherapy or radiation treatment, such that lower doses of either may be used, decreasing the overall toxicity to normal cells while maintaining equivalent efficacy in treating the tumor. ([0120], claims, 5, 8-9). Anti-ADAM12 antibodies can also be used in the form of antibody conjugates to directly deliver cancer agents with a lethal effect on the tumor. Such agents include radionuclides, toxins, and chemotherapeutics [0119].The antibodies of the present invention may be administered alone or in combination with other molecules for use as a therapeutic, for example, by linking the antibody to cytotoxic agents or radioactive molecules. Radioactive antibodies and antibodies comprising a cytotoxic microbial, plant, or chemical compound that are specific to a cancer cell, diseased cell, or other target cell may be able to deliver a sufficient dose of radioactivity or toxin to kill the cell [0202]. The mature form of ADAMl 2L is overexpressed at the surface of cancer cells and is not normally expressed at high levels in healthy, non-pregnant adults [0213]. The tumor is chosen from a lung tumor, a colorectal tumor, a breast tumor, a bladder tumor, a pancreatic tumor, and a stomach tumor ([031 ] and claims 55-58). A modulator composition comprising a pharmaceutically acceptable carrier and a modulator, wherein the modulator is the antibody (see published claim 40, [013]). A kit comprising the antibody of claim 5 and instructions for performing the method (published claims 54, 80, [029], [033]).
The reference teachings differ from the claimed invention only in the recitation of that the specific toxin recited in claim 1 and second anti-tumor compound is an antibody in claim 3 and the antibody is monoclonal antibody tht targets VEGF in claim 5.
The `251 publication teaches to the anti-cancer agent is selected from cytotoxic and cytostatic proteins and peptides capable of killing a target cell or inhibiting its growth or proliferation. The `251 publication provides that the toxin is selected from the group consisting of a bacterial toxin, a plant toxin, a fungal toxin, and a combination thereof. The bacterial toxin is selected from the group consisting of diphtheria toxin, Pseudomonas exotoxin, cholera toxin, anthrax toxin, botulinum toxin, pertussis toxin, E. coli enterotoxin, and shiga toxin. The plant toxin is selected from the group consisting of ricin, modeccin, abrin, volkensin and viscumin. The fungal toxin is selected from the group consisting of α-sarcin, restrictocin, mitogillin, enomycin, RNase T1 and phenomycin [0022].
Hurwitz at al that the addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer (mCRC) (abstract).
The `576 publication teaches a compound and/or a prodrug compound of the invention can be used in combination with an angiogenesis inhibitor including but not limited to Avastin (bevacizumab) and similar therapeutics. In one version of the combination treatment methods, a subject is treated with an angiogenesis inhibitor and subsequently treated with a compound and/or a prodrug compound of the invention. In one version of these combination methods of treatment using an angiogenesis inhibitor, the method is used to treat breast cancer [0161]. The present invention provides a method of cancer treatment, wherein there is synergy between a compound and/or a prodrug compound of the invention and another anticancer agent. Two drugs can be said to possess therapeutic synergy if a combination dose regimen of the two drugs produces a significantly better tumor cell kill than the sum of the single Agents at optimal or maximum tolerated doses. The "degree of synergy" can be defined as net log of tumor cell kill by the optimum combination regimen minus net log of tumor cell kill by the optimal dose of the most active single Agent. Differences in cell kill of greater than ten-fold (one log) are considered conclusively indicative of therapeutic synergy [0167].
Those skilled in the art would have had a reason to use the specific toxins taught by `251 publication as a substitute for the toxins taught by `903 publication in the methods of killing cancer in combination with the radionuclides, toxins, and chemotherapeutics anti-ADAM12 antibodies conjugates taught by the `903 publication in view of the `251 publication with the anti-angiogenesis inhibitor bevacizumab (Avastin) taught by Hurwitz et al and the `576 publication to multitarget treatment of mCRC and breast cancer because the combination would result in improvement in survival of patient with mCRC and breast cancer. It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06.
The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combine for their common known purpose. Section MPEP 2144.07.
When considering obviousness of a combination of known elements, the operative question is thus "whether the improvement is more than the predictable use of prior art elements according to their established functions." KSR at 418. In the instant case, the inventors merely used routine research methods to prove what was already believed to be the case.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments, filed 05/19/2025, have been fully considered, but have not been found convincing.
Applicant points to Dr. Peduto's Declaration, Applicant's claimed immunoconjugate is expected to show a surprising effect on the tumor stromal capsule-depleting ADAM12 expressing stromal cells delays tumor growth improves the vasculature, tumor perfusion and T cell infiltration in the core of the tumor and limits macrophage polarization towards an immunosuppressive M2 phenotype. Declaration at 20-25. The antitumoral effect is surprising because the depletion of ADAM12+ stroma cells (ADAM12+ CAFs) depletes less than 10 % of CAFs, whereas the majority of CAFs (more than 90%) do not express ADAM12 (ADAM12- CAFs) and cannot be depleted. For these reasons, the claimed immunoconjugate has properties that are unexpected in view of the cited prior art. The Examiner appears to agree that Applicant has unexpected results, but that these unexpected results are "not commensurate in scope with the invention as claims." (Office Action at 7.) Applicant disagrees.
Applicant showed that it was possible to improve the vasculature, tumor perfusion and T cell infiltration in the central region of the tumor (core of the tumor) by depleting ADAM12 expressing stromal cells. Applicant's unexpected findings provide a rationale for a method of second-line adjuvant therapy of cancer to limit resistance to first-line cancer treatments because first-line cancer treatments often fail or become inefficient after some time because drugs and tumor specific T cells cannot access anymore the core of the tumor (paragraph [0032], page 2 ; para [142] and [144], page 10 of the present application). While previous treatment of a patient's tumor with a first anti-tumor compound or therapy was measured as lacking effectiveness because the first compound and tumor specific T cells could not access anymore the core of the tumor (resistance to first-line cancer treatment), inventor's findings indicate that depletion of ADAM12 expressing stromal cells provides effectiveness to subsequent treatment of the patient's tumor with a second antitumor compound because depletion of ADAM12 expressing stromal cells improves the vasculature, tumor perfusion and T cell infiltration in the central region of the tumor (second-line adjuvant therapy of cancer).
The Peduto declaration under 37 CFR §1.132 filed 12/12/2024 is insufficient to overcome the 103 rejection on record because the showing of surprising results in the specification cannot be clearly equated with the claimed invention. The showing of unexpected results is not commensurate in scope with the invention as claimed. The showing unexpected results must be based on evidence, not merely argument or speculation. The claims are directed to a combination of pharmaceutical compositions comprising an immunoconjugate comprises a genus of monoclonal antibody or antibody fragment thereof that binds ADAM12 on the surface of stromal cells and a toxin that kills ADAM12 expressing stromal cells and depletes ADAM12 expressing stromal cells, and a specific humanized monoclonal antibody that targets VEGF, bevacizumab. While the showings of surprising unexpected results are limited to genetic murine models of cancer: melanoma (M05 cell line; Example 2 (para [0147], p.10)) and pancreatic cancer (RIP-Tag2 mice that express SV40 under control of the insulin promotor; Example 1 (para [0146], p.10)). See enclosed Declaration at 7. No humanized monoclonal anti-VEGF antibodies are used. No monoclonal anti-ADAM12 antibodies are used. No immunoconjugate comprising monoclonal anti-ADAM12 antibody and toxin are used. Diphtheria toxin (DT) and immunoconjugates comprising anti-ADAM12 antibodies and toxin are very different molecules. The declaration does not show the effect of the claimed combination of humanized monoclonal anti-VEGF antibody, bevacizumab, and immunoconjugates comprising monoclonal anti-ADAM12 antibodies and toxins as recited in the claims.
The results do not compare the effect of immunoconjugates with/out monoclonal anti-VEGF antibodies and monoclonal anti-VEGF antibodies with/out the immunoconjugates to show surprising unexpected results of the claimed combination.
Importantly, the asserted unexpected results are already possessed by the prior art irrespective of the mechanism of action. The `903 publication teaches that anti-ADAM 12 antibodies can act to sensitize the cancer cells to chemotherapy or radiation, allowing for more efficient tumor killing. Alternatively, anti-ADAM12 antibodies can act in synergy with chemotherapy or radiation treatment, such that lower doses of either may be used, decreasing the overall toxicity to normal cells while maintaining equivalent efficacy in treating the tumor. ([0120], claims, 5, 8-9). Anti-ADAM12 antibodies can also be used in the form of antibody conjugates to directly deliver cancer agents with a lethal effect on the tumor. Such agents include toxins [0119].The antibodies of the present invention may be administered alone or in combination with other molecules for use as a therapeutic, for example, by linking the antibody to cytotoxic agents. Radioactive antibodies and antibodies comprising a cytotoxic microbial, plant, or chemical compound that are specific to a cancer cell, diseased cell, or other target cell may be able to deliver a sufficient dose of radioactivity or toxin to kill the cell [0202]. The mature form of ADAMl 2L is overexpressed at the surface of cancer cells and is not normally expressed at high levels in healthy, non-pregnant adults [0213].
Moreover, Hurwitz at al that the addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer (mCRC) (abstract).
Those skilled in the art would have had a reason to use the specific toxins taught by `251 publication as a substitute for the toxins taught by `903 publication in the methods of killing cancer in combination with the radionuclides, toxins, and chemotherapeutics anti-ADAM12 antibodies conjugates taught by the `903 publication in view of the `251 publication plus the anti-angiogenesis inhibitor bevacizumab (Avastin) taught by Hurwitz et al and the `576 publication to multitarget treatment of mCRC and breast cancer because the combination would result in improvement in survival of patient with mCRC and breast cancer with reasonable expectation of success. It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06.
As noted by the court in this case, “’by definition, any superior property must be unexpected to be considered as evidence of non-obviousness’ and that unexpected results ‘evidence must fail [if] the record is devoid of any evidence of what the skilled artisan would have expected.’” Id. at 52, citing Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007). Thus, if a practitioner is making an argument for unexpected results, it must truly be unexpected—not already disclosed in the prior art—and be supported by factual evidence. See also, Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1306 (Fed. Cir. 2015)(“We also conclude that the district court did not clearly err in finding that the claimed formulation exhibited ‘unexpected results,’ which differed in kind, not just in degree, from the prior art.”). In other words, the unexpectedness must be sufficient “to secure the validity of the claims in suit.” Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371, 1381 (Fed. Cir. 2005).
In order for an examiner to credit objective evidence, the applicant must establish a nexus between the evidence and the merits of the invention. This “nexus” between the evidence and the claimed invention “is a legally and factually sufficient connection.” Henny Penny Corp. v. Frymaster LLC, 938 F.3d 1324, 1332 (Fed. Cir. 2019). If the court finds that the objective evidence is attributable to something other than the invention, such as marketing and/or non-invention features, there is no nexus to the claimed invention and the objective evidence will fail to rebut a prima facie case of obviousness.
Applicant submits that claim 1, as amended, recites specific monoclonal antibodies (bevacizumab, ranibizumab, nivolumab, pembrolizumab and ipilimumab), which are well-known to have clinical effectiveness, and which would be expected to have improved activity under the conditions of improved vasculature, tumor perfusion and T cell infiltration in the central region of the tumor since these therapies often fail or become inefficient after some time because they cannot access anymore the core of the tumor.
This is not found persuasive because the claimed methods are directed to a combination therapy anti-ADAM12 antibody immunoconjugates with toxin and Bev, while the showing is limited to the depletion of ADAM12+ stroma cells (ADAM12+ CAFs) using genetic murine models (ADAM12-DTR (M12-DTR)) injected with melanoma cells leading to decrease in tumor growth (see Fig. 4 and 5). The teachings of WO 2006014903 which teaches the use of anti-ADAM12 antibody conjugated to toxins is simply closer to Applicant’s claimed invention than the showing of unexpected results with the genetic murine models. In both models resulted in killing /decreasing tumor.
WO 2006/014903 does not disclose a combination of an immunoconjugate comprising a monoclonal antibody or antibody fragment thereof that binds ADAM12 on the surface of stromal cells and a toxin that kills ADAM12 expressing stromal cells and a second anti-tumor compound selected from bevacizumab, ranibizumab, nivolumab, pembrolizumab and ipilimumab. Neither Hurwitz et al (2004) nor US 20080214576 remedy this deficiency because neither reference demonstrates the surprising effect of the claimed immunoconjugate on the tumor stromal capsule - that depleting ADAM12 expressing stromal cells delays tumor growth by improving the vasculature, tumor perfusion and T cell infiltration in the central region of the tumor (core of the tumor) and limits macrophage polarization towards an immunosuppressive M2 phenotype, allowing improved activity of the recited monoclonal antibodies. Accordingly, Applicant respectfully requests withdrawal of the rejection.
However, Applicant’s specification and unexpected results suffer from the same deficiency as WO 2006/014903. If the specification /”unexpected results” showings are enabled so is the prior art of WO 2006/014903. However, if WO 2006/014903 is not enabled, neither is the specification / “unexpected results” showings. The specification does not go beyond the teachings of WO 2006/014903. The administration of the anti-ADAM12 antibody conjugated to toxins taught by WO 2006/014903 would inherently binds ADAM12 on the surface of stromal cells which would kill ADAM12 expressing stromal cells as is evidenced by Applicant argument that “Applicant’s claimed immunoconjugate is expected to show a surprising effect on the tumor stromal capsule-depleting ADAM12 expressing stromal cells delays tumor growth improves the vasculature, tumor perfusion and T cell infiltration in the core of the tumor and limits macrophage polarizing towards an immunosuppressive M2 phenotype” (see Applicant’s Remarks page 9, 1st ¶ and Dr. Peduto’s Declaration at ¶¶20-25).
It remains the Examiner’s position that those skilled in the art would have had a reason to use the specific toxins taught by `251 publication as a substitute for the toxins taught by `903 publication in the methods of killing cancer in combination with the radionuclides, toxins, and chemotherapeutics anti-ADAM12 antibodies conjugates taught by the `903 publication in view of the `251 publication with the anti-angiogenesis inhibitor bevacizumab (Avastin) taught by Hurwitz et al and the `576 publication to multitarget treatment of mCRC and breast cancer because the combination would result in improvement in survival of patient with mCRC and breast cancer. It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06.
The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combine for their common known purpose. Section MPEP 2144.07.
When considering obviousness of a combination of known elements, the operative question is thus "whether the improvement is more than the predictable use of prior art elements according to their established functions." KSR at 418. In the instant case, the inventors merely used routine research methods to prove what was already believed to be the case.
8. No claim is allowed.
9. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Di Carlo et al. Depletion of slow-cycling PDGFRα+ ADAM12+ mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis. Nature Immunology, 24:1867-1878, November 2023.
10. The references cited on PTO-892 were provided by Applicant on 05/19/2025 and will not be supplied.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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August 14, 2025
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644