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 .
Applicant’s election without traverse of group II and the species cancer, sarcoma, PD1, IL-17B, pembrolizumab, and an antibody directed against IL-17B in the reply filed on 1/20/26 is acknowledged.
Claims 1, 7, 8, 16, 25, and 26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/20/26.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3-6, 9, 10, 15, 19-24 are 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to a method of delivering an inhibitor of PD1 or any ligand thereof and an inhibitor of IL-17B or any receptor thereof.
The specification does not adequately describe the structure required for the function for an inhibitor of PD1 or any ligand thereof and an inhibitor of IL-17B or any receptor thereof. Without further description of the structure required, one would not be able to readily envision which compounds necessarily have the structure to function as an inhibitor of PD1 or any ligand thereof and an inhibitor of IL-17B or any receptor thereof.
The specification discloses species of PD1/PDL1 antibodies and IL-17B antibodies. The species of the specification are not representative of the entire claimed genus.
Not only does the specification not adequately describe the structure required for the compound to be an inhibitor of PD1, and ligand thereof, IL-17B, or any receptor thereof, but the specification discloses that the term IL-17B has its general meaning in the art and a polypeptide having a sequence according to GenBank Acc. No. NP_001304916.1 or NP_055258.1, the product of the human IL-17B gene, and include all of the variants, isoforms or species homologs of IL-17B (page 9). The specification does not adequately describe the genus of variants, isoforms or species homologs of IL-17B and therefore one would not be able to readily envision which compounds are inhibitors of this genus.
Although claim 22 recites specific PD1 inhibitors and claim 23 recites an antibody directed against IL-17B, there are no claims that require this combination.
For example, the claims encompass any compound that acts upon any target that has the secondary effect of inhibition of PD1, any ligand thereof, IL-17B, or any receptor thereof, which is a genus of compounds that have not been adequately described in the instant specification.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for compounds that have the structure to function as inhibitors of PD1, any ligand thereof, IL-17B, or any receptor thereof. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claims 3-6, 9, 10, 15, 19-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of inhibiting PD1 and IL-17B and to a method of treating fibrosarcoma, does not reasonably provide enablement for a method of treating any cancer via delivery of any inhibitor of PD1 or any inhibitor of IL-17B. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method of treating any cancer via delivery of any inhibitor of PD1, any ligand thereof, IL-17B, or any receptor thereof.
However, the specification does not draw an adequate nexus between inhibition of PD1, any ligand thereof, IL-17B, or any receptor thereof and the predictable outcome of treating any possible cancer, which encompasses an enormous genus of cancers that have not been shown to be reliant upon PD1, any ligand thereof, IL-17B, or any receptor thereof alone.
The specification demonstrates i.p. injection of anti-PD1 antibody in IL-17B knockout mice in a MCA205 fibrosarcoma model with a significant tumor growth delay (Example 1); and treatment of mice subcutaneously grafted with MCA205 cells with anti-IL-17B antibody and anti-PD1 antibody with a significant increase to the response to anti-PD1 therapy alone (Example 3); and i.p. injection of anti-PD1 antibody in IL-17B knockout mice in a B16K1 melanoma model with a significant tumor growth delay (Example 4).
Treatment of fibrosarcoma with a combination of anti-IL-17B antibody and anti-PD1 antibody is not commensurate in scope with the treatment of any possible cancer. The knockout model of IL-17B is not commensurate in scope with any level of inhibition via delivery of any IL-7B inhibitor or any IL-17B receptor inhibitor.
Additionally, there is no guidance in the specification as filed that teaches how to deliver the instantly recited genus of inhibitors, each having different delivery challenges, and predictably treat any cancer in vivo.
For example, siRNAs, a single species of the instant inhibitors, the instant siRNAs are not required to have any specific structural relationship with any specific target sequence. The instant claims not only encompass targeting any target that has the secondary effect of inhibiting any inhibitor of PD1, any ligand thereof, IL-17B, or any receptor thereof, but also encompasses siRNAs targeted to any possible region of any target sequence. It is known in the siRNA field that not any siRNA to any target sequence will result in inhibitory effect. Even from those that are inhibitory to PD1, any ligand thereof, IL-17B, or any receptor thereof, not all of this pool would predictably result in treatment effects in vivo.
The specification is not enabled for mediating RNA interference in vivo by the broadly recited methods, as delivery and effective action therein is known in the art to be unpredictable with regards to dsRNA duplexes. Activity in vitro is not predictable of the in vivo therapeutic effect in the in vivo complex environment.
For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
Fujita et al. (Int. J. Mol. Sci. 2015, 16, 5254-5270) teach that two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications (page 5254). Fujita et al. teach that the success of an RNAi-based therapy in clinical trials rests on careful selection of target genes and miRNAs. Moreover, we suggest that a delivery route, sophisticated delivery carriers, chemical modification, and modified RNAi platforms are needed to enhance RNAi effects in cancer cells (pages 5262-5263).
Friedrich et al. (BioDrugs (2022) 36:549–571) teach that still, the development of siRNA therapeutics faces several challenges and issues, including the definition of optimal siRNAs in terms of target, sequence, and chemical modifications, siRNA delivery to its intended site of action, and the absence of unspecific off-target effects (Abstract). Friedrich et al. teach that the use of short siRNA is preferred because longer siRNAs can provoke an inflammatory antiviral immune response (page 551).
These references illustrate the delivery and design challenges of siRNAs, which are a single species of inhibitory compounds. The claims are directed to any type of inhibitory compound of any structure, each class having its own challenges.
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art (a single species of the instant inhibitors) for therapeutic in vivo applications and design. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating any cancer via broad systemic delivery of a broad genus of agents that act via different mechanisms and have different levels of activity encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any possible inhibitor of PD1, any ligand thereof, IL-17B, or any receptor in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of any possible cancer, each having its own etiology. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3-6, 9, 15, and 19-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yazdanifar et al. (Curr Trends Immunol. 2016 ; 17: 95–115).
The reference is considered as enabled as the instant specification.
Yazdanifar et al. teach that pancreatic ductal adenocarcinoma (PDA), which accounts for over 90% of pancreatic cancers, remains treatment refractory (page 9).
Yazdanifar et al. teach that two PD-1 inhibitors, nivolumab and pembrolizumab, have been tried in PDA patients. Using these mAbs as single agent treatments has not proved very effective, and thus new trials combining these antibodies with other agents such as vaccines or chemotherapy have emerged (page 10).
Yazdanifar et al. teach that mAb against IL-17B receptor signaling showed improved survival in an orthotropic xenograft model of PDA (page 10).
Given that Yazdanifar et al. teach that pembrolizumab, a PD-1 inhibitor, has not proven to be very effective alone for treatment of PDA and should be combined with other agents; and teach that another agent that has resulted in increased survival in PDA is a mAB against IL-17B receptor signaling, it would have been obvious to deliver a combination of pembrolizumab and a mAB against IL-17B receptor signaling with a reasonable expectation of treatment of PDA (instant claims 3 and 20-24).
It would have been obvious to deliver the antibody together or after treatment with pembrolizumab as a matter of design choice given that both agents are being delivered for treatment of the same cancer (instant claim 15); and it would have been obvious to deliver the antibody after treatment with pembrolizumab if the treatment with pembrolizumab alone is not sufficient (due to drug resistance) in order to save the expense of an additional treatment if not necessary (instant claims 4, 6, and 9).
It is noted that claim 5 recites an outcome rather than a required method step. Delivery of the instantly recited agents would necessarily result in the recited outcome.
Regarding instant claim 19, it would have been a matter of design choice to incorporate the inhibitor of PD1 in the combination therapy at an inferior amount to a monotherapy. Additionally, the claim is not directed to any specific amount in either of the compositions and there is no static known amount of the PD1 inhibitor in the monotherapy to compare the amount in the combination therapy to.
With regards to elected species “sarcoma”:
Claim(s) 3-6, 9, 10, 15, and 19-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shaked et al. (WO 2018/225062 A1), in view of Alberici et al. (WO 2013/186236 A1).
The references are considered as enabled as the instant specification.
Shaked et al. teach: As used herein, the term "a cancer therapy" may be used interchangeably with the term "a cancer therapy modality", and include plural reference, namely, one single modality therapy or a combination of two or more modality therapies. In accordance with the invention, the cancer therapy is related to treatment of all types of cancer, primary or metastatic, selected from sarcomas, carcinomas, myelomas, lymphomas and leukemias. In certain embodiments, the cancer is of the sarcoma type, e.g. soft tissue sarcoma, osteosarcoma (page 4) (instant claim 10).
Shaked et al. teach: As used herein, the terms "a cancer therapy" and "a cancer therapy modality" refer to any modality of cancer therapy including, but without being limited to, chemotherapy, radiation therapy, surgery, targeted therapy (including all types of immunotherapy, anti-angiogenic therapy, hormonal therapy, and photodynamic therapy), thermotherapy, and combinations thereof.
In certain embodiments, the chemotherapy is mono-chemotherapy, i.e., treatment with one single chemotherapy drug. In certain other embodiments, the chemotherapy is combination chemotherapy, i.e., treatment with two, three, four or more chemotherapy drugs (pages 4-5).
In certain embodiments, the fold change determined for pro-tumorigenic factors is predictive of the patient's non-favorable response to the drug and the medical oncologist's decision may be to change the treatment using a different drug, or to use a combination of two or more drugs of the same modality, e.g., two chemotherapeutic drugs, or a combination of the drug with a drug used in another cancer therapy modality, for example, a combination of a chemotherapeutic drug with a drug used in targeted cancer therapy (instant claim 3).
Shaked et al. teach: In certain embodiments, the targeted cancer therapy is immunotherapy with monoclonal antibodies (mAbs) that trigger the body's immune system to fight and destroy cancer cells. In certain embodiments, the mAb binds to a target antigen on the surface of cancer cells and activates the immune system to attack the cancer cells or to block protein that helps the cancer cells grow and is located within or on surface of tumors or in the tumor microenvironment (page 7).
In certain embodiments, the targeted cancer therapy is immunotherapy with immune checkpoint inhibitors (ICI) including, but not limited to, inhibitors to the checkpoints PD-1 or its known ligand, PD-L1, or CTLA-4 that are found on T cells and other immune cells such as macrophages. The ICI are preferably monoclonal antibodies (mAbs) and include pembrolizumab (Keytruda; formerly called lambrolizumab) (page 8) (instant claims 3, 4, 21, 22, and 24).
Thus, in certain embodiments, the cancer therapy is chemotherapy and the kit will comprise monoclonal antibodies that specifically bind to pro-tumorigenic factors identified according to the method of the invention to be generated by the host in response to chemotherapy. The kit will of course comprise additional antibodies for binding to potential candidates pro-tumorigenic factors (page 16).
The circulating factor is IL-17B (page 14) (instant claims 3, 4, 20, 23, and 24). Given that Shaked et al. clearly teaches combining the various treatments taught by Shaked et al., it would have been obvious to deliver pembrolizumab with an antibody against IL-17B for the treatment of sarcoma.
It would have been obvious to deliver the antibody together or after treatment with pembrolizumab as a matter of design choice given that both agents are being delivered for treatment of the same cancer (instant claim 15); and it would have been obvious to deliver the antibody after treatment with pembrolizumab if the treatment with pembrolizumab alone is not sufficient (due to drug resistance) in order to save the expense of an additional treatment if not necessary (instant claims 4, 6, and 9).
Alberici et al. is additional evidence that it was known to deliver an inhibitor of IL-17B including antibodies against IL-17B for the treatment of sarcoma (pages 3 and 8-11).
It is noted that claim 5 recites an outcome rather than a required method step. Delivery of the instantly recited agents would necessarily result in the recited outcome.
Regarding instant claim 19, it would have been a matter of design choice to incorporate the inhibitor of PD1 in the combination therapy at an inferior amount to a monotherapy. Additionally, the claim is not directed to any specific amount in either of the compositions and there is no static known amount of the PD1 inhibitor in the monotherapy to compare the amount in the combination therapy to.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636