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 .
Restriction/Election
Applicant's election with traverse of Group II, claims 15-23, and the species duvalumab and SEQ ID NO: 1 in the reply filed on 01/13/26 is acknowledged. The traversal is on the ground(s) that there is no serious search burden, which must be met along with the independent and distinct test. This is not found persuasive because claim 1 requires additional steps, including obtaining and exposing a T-cell ex-vivo or in-vitro, which is entirely different than administering the VIP antagonist, immune checkpoint inhibitor and anti-cancer antibody antagonist to subject to enhance immune response to treat cancer in the subject. Furthermore, the dependent claims require different “anti-cancer” antibodies to also be exposed to the cell before treatment. These additional limitations create a significant burden, as this additional exposure step is not required for administering the VIP antagonist, immune checkpoint inhibitor and anti-cancer antibody directly to a subject for cancer treatment.
Upon search, the art has not specifically taught the combination of a VIP antagonist with an immune point inhibitor being exposed to the T-cell together ex-vivo or in vitro, which further establishes the search burden.
The requirement is still deemed proper and is therefore made FINAL.
Regarding the species election, however, the search revealed art reading on the immune checkpoint inhibitors of claims 16-19, and the VIP antagonists of claims 21 and 22. As such, these claims were examined, as they are part of the elected invention, and there was no search burden in the species search. Claims 1-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/13/26. Claims 14-23 are under examination. An office action on the merits follows.
Claim Rejections 35 USC112 1st Paragraph
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.
Claims 15-23 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 treating certain PD-L1, PD-1 and CTLA-4 expressing cancers with the disclosed immune checkpoint inhibitors, anti-cancer antibodies and VIP antagonists, does not reasonably provide enablement for treating all cancers with any anti-immune checkpoint/ VIP antagonist/anti-cancer antibody combination. 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 use the invention commensurate in scope with these claims.
A more detailed scope of the enabled cancers treatable with the claimed combination of VIP antagonists, checkpoint inhibitors and anti-cancer antibodies will be discussed in the analysis that follows.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue" These factors include, but are not limited to:
(1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) 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) (reversing the PTO's determination that claims directed to methods for detection of hepatitis B surface antigens did not satisfy the enablement requirement). In Wands, the court noted that there was no disagreement as to the facts, but merely a disagreement as to the interpretation of the data and the conclusion to be made from the facts. In re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-07. The Court held that the specification was enabling with respect to the claims at issue and found that "there was considerable direction and guidance" in the specification; there was "a high level of skill in the art at the time the application was filed;" and "all of the methods needed to practice the invention were well known." 858 F.2d at 740, 8 USPQ2d at 1406. After considering all the factors related to the enablement issue, the court concluded that "it would not require undue experimentation to obtain antibodies needed to practice the claimed invention." Id., 8 USPQ2d at 1407.
(1) The nature of the invention and (5) The breadth of the claims:
The invention is drawn to a method of enhancing an immune response to cancer or treating cancer with a combination of a VIP antagonist, anti-cancer antibody and immune checkpoint inhibitor.
The claims are very broad in that they encompass all types of cancer with insufficient support to show that any immune check-point inhibitor with any VIP antagonist and any anti-cancer antibody will effectively treat that type of cancer. Applicant has not provided sufficient enabling disclosure as to how one of ordinary skill in the art would treat all cancers with any type of immune checkpoint inhibitor, as each type of inhibitor is distinct and specific to the molecule despite the broad definition of inhibiting any point along and immune pathway, only CTLA-4 and PD-1/PD-1L inhibitors have been identified in the art for treating some cancers (As evidenced by Siedel et al. 2018, Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Frontiers in oncology, 8: 86). Further, applicant’s specification only provides examples of treating melanoma and pancreatic cancer with anti-PDL/PDL1 antibodies and the VIP antagonists, SEQ ID NOs: 1 and 3. Additionally, applicants do not provide any limiting a definition of the scope of an anti-cancer antibody, which means that it can encompass any anti- PDL-1 and anti-VIP antibody, combined with any antibody known in the art to be effective for treating any cancer. This is much broader than the “anti-cancer” antibodies exemplified in the specification, as there is no limiting definition of “anti-cancer antibody.”.
(2) The state of the prior art:
As to the enablement of treating cancer in general, neither the prior art nor the specification support this scope of enablement. For example, Yao states that PD-1 seemed to play a distinct role in lung cancer, as blockade of PD-1 instead promoted tumor cells proliferation, meaning it had to opposite in this particular cancer (2018; Cancer Cell-Intrinsic PD-1 and Implications in Combinatorial Immunotherapy. Front. Immunol. 9:1774). Additionally, as discussed above, the only cancers known in the art to be treatable with anti-PD1/PDL1 antibodies are non-small cell lung cancer, melanoma, lymphoma, bladder cancer, kidney cancer, squamous cell carcinoma, adenocarcinoma, leukemia and breast cancer (As evidenced by MedLine/National Institutes of Health, PDL1 Immunotherapy Tests, last visited, 02/19/26; Cao et al., Front. Immunol., Review; 2023; 14:1265299).
It is clear from the prior art that the role of immune check points antibodies in general and anti-PDL1/PDL or CLA4 antibodies is not established for every type of cancer, which shows that applicant’s claims drawn to treating all cancers with all inhibitors/antagonists/antibodies claimed has not been established in the prior art or the specification. Furthermore, the scope of anti-cancer antibodies can broadly include and antibody that treats cancer in any form. As such, the method of treating cancer must be accompanied by evidence of efficacy in the prior art or specifically established in the instant application in order to be enabled.
(3) The relative skill of those in the art:
The relative skill of those in the art is high.
(4) The predictability or unpredictability of the art:
The claims do not identify what cancers are considered to be treatable by administration of the claimed VIP agonists, anti-cancer antibodies and immune check-point molecules. As discussed above, the state of the prior art shows that there are numerous types of cancer, but there is limited knowledge of check point inhibitors, VIP inhibitors and antibodies that can treat the vast array of cancers. Based on the prior art teachings, some cancers may be treated with such antibodies, but administration of these may have the opposite effect on other types, as discussed by Yao.
The prior art does not clarify a particular role for immune checkpoint inhibitors overall. As a result, one of ordinary skill in the art would not be able to predict based on the prior art and the specification which diseases can be treated with the types of VIP agonists and antibodies to immune checkpoint molecules.
(6) The amount of direction or guidance presented and (7) The presence or absence of working examples:
Applicants have claimed to be able to treat all cancers with all VIP agonists combined with any anti-cancer antibody and any immune checkpoint inhibitor; however, applicants only list: lung cancer, renal cancer, leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, myeloma, bladder cancer, gastric cancer, esophageal cancer glioblastoma, colon cancer, breast cancer, pancreatic cancer, melanoma and prostate cancer. Of these listed types of cancer, applicants have only reduced methods of treatment of melanoma and pancreatic tumor treatment to practice. There is insufficient support in the specification that shows treatment or all cancers with the claimed combination are enabled.
There is no guidance given as to what further defines the genus of cancers or even the types of cancer are considered to express PD1L/PD1 and CTL4, such that the claimed immunotherapy would be effective.
(8) The quantity of experimentation necessary:
As discussed above, the predictability of what will be treatable by administering any one of the VIP antagonists and immune checkpoint inhibitors is low, and it would require experimentation on patient classes which have been administered each type of antibody to immune check-point molecules. It would require “undue” experimentation to allow one of ordinary skill in the art to determine which cancers are treatable by the claimed combination because of the amount of variability in the response different types of cancer cells to different antibodies. Thus, the claims are not enabled for treating all cancers with the claimed combination.
As such, applicants are only enabled for treating pancreatic cancer, as shown in the specification (melanoma and pancreatic cancer), and those known in the art (non-small cell lung cancer, leukemia, melanoma, lymphoma, bladder cancer, kidney cancer and breast cancer), with VIP antagonists and the immune checkpoint inhibitors disclosed in the specification and only the anti-cancer antibodies listed in claim 20, as there is no definition of the scope of what anti-cancer antibodies encompasses disclosed in the specification.
Claim Rejections 35 USC 103(A)(1)
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.
Claims 15-19, 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Waller et al. (US2017/0258904) in view of Neville et al. (WO2018/031507).
Waller teaches methods of treating or preventing a viral infection comprising administering a VIP antagonist to a subject at risk of, exhibiting symptoms of, or diagnosed with a viral infection, where the subject is immune compromised or the subject is an allogeneic bone marrow transplant donor or recipient, diagnosed with cancer and receiving an immunosuppressive drug [0007]. This reference further teaches that VIP modulates the expression of the PD-1 and PD-L1 co-inhibitory molecules that regulate immune polarization and survival of T-cells [0049]. This reference teaches that up-regulation of the PD-L1/L2-PD-1 pathway has been associated with immunosuppression due to cell-cycle arrest, and death of T-cells, either through the direct engagement of a death pathway or indirectly by down-regulating survival signals and growth factors and that PD-L1/L2 expression on DC is associated with reduced expression of CD40, CD80, and CD86 and increased IL-10 production [0049]. This reference further teaches that methods of treating cancer administer the VIP agonist, SEQ ID NO: 9, which is identical to the instantly claimed SEQ ID NO: 1 and the modified SEQ ID NO: 9 of the instant claims. Waller further teaches that treatment of leukemia, breast, lung, colon, skin, kidney, prostate, and other cancers can be treated by administering VIP antagonist in combination with cancer antigens [0058]. This reference further teaches that the VIP antagonist (antibody) specifically binds VIP or VIP receptor such as VPAC1, VPAC2, and PAC1, but should not be construed as being limited solely one type of antibody and that certain embodiments of the disclosure also encompass polyclonal, monoclonal, synthetic antibodies, and the like, which are all anti-cancer antibodies [0072-0074].
The difference between the prior art and the instant claims is that the prior art does not teach administering an immune checkpoint inhibitor with the VIP and ani-cancer antibodies of Waller.
Neville teaches methods of treating patients suffering from cancer using a combination of 1) an immunomodulatory agent; 2) a check point inhibitor; and 3) a cancer antigen releasing therapy where the immunomodulatory agent is an anti-CD3 immunotoxin, the check point inhibitor inhibits the interaction of PD-1 and PD-L1 and the cancer antigen releasing therapy is radiation [001-002]. This reference further teaches that cancer cells which express PD-L1/PD1 on their surfaces and are camouflaged as normal cells and are not attacked by the immune system, which allows them to evade immune clearance [0002]. Neville also teaches that immune check point inhibitor antibodies have been developed that block the interaction of PD-L1 and PD-1 by binding to one or the other of these proteins and sterically inhibiting their interaction, which prevents PD-L1/PD-1 bearing cancers from evading the immune system, resulting in recognition and destruction [0002]. This reference further teaches that such check-point inhibitor antibodies include anti-PD-1 antibodies, such as Pembrolizumab and Nivolumab; anti-PD-L1 antibodies, such as Avelumab and Durvalumab; and anti-CTLA4 antibodies such as ipilimumab [0025]. This reference further teaches that such cancer treatable with these antibodies include pancreatic neuroendocrine tumors; kidney (e.g. renal cell cancer), leukemia, liver cancer, lung cancer (non-small cell); lymphomas, breast cancer, bladder cancer, melanoma and myeloma [0003, 0007, 0046].
It would have been obvious to one of ordinary skill in the art at the effective filing date of the invention to have taken the method of Waller for administering VIP antibodies and combined it with the method of Neville because both teach treating cancer with anti-PLD-1 antibodies, and Waller teaches that VIP modulates the expression of the PD-1 and PD-L1 co-inhibitory molecules that regulate immune polarization and survival of T-cells. One would be motivated to combine the immune checkpoint inhibitors with the VIP agonists of Waller because Waller teaches that VIP antagonists regulate PDL-1, which Neville teaches is responsible for blocking the destruction of tumor cells. As such, there is a reasonable expectation of success, that the combination of the will effectively target and enhance the immune repose as well as treat cancer.
This renders obvious claim 15 by teaching the administration of VIP antagonists (SEQ ID NO: 1 and 9) with an immune check-point inhibitor and various anti-PDL-1 and anti-cancer antibodies, including anti-PD-1 antibodies, anti-CTLA4 antibodies and more than one type of anti-PDL-1 and VIP antibody for enhancing immune response and treating cancer. Additionally, Waller teaches that the compositions do not need to be limited to one type of antibody, and Neville further renders it obvious to administer multiple antibodies to block the interaction of PD-L1 and PD-1 for enhancing immune response and treating cancer. Claims 16-19 are met because Neville teaches that suitable immune checkpoint inhibitors include anti-PD1 antibodies, including pembrolizumab, nivolumab, pidilizumab; exemplary anti-PD-Ll antibodies, including tezolizumab, avelumab, and durvalumab; and exemplary anti-CTLA-4 antibodies, including ipilimumab [0024-0026]. Claims 21 and 22 are met because Waller teaches SEQ ID NO: 1 and SEQ ID NO: 9.
Claims 15-22 are rejected under 35 U.S.C. 103 as being unpatentable over Waller et al. (US2017/0258904) in view of Neville et al. (WO2018/031507), and in further view of Xie et al. (Blood Cancer Journal; 2017, volume 7, e567, p. 1-9)
The teachings of Waller and Neville have been described supra.
The difference between the prior art and the instant claims is that the prior art does not teach administering any of the recited anti-cancer antibodies of claim 20, such as CD123.
Xie teaches that overexpression of the interleukin-3 receptor-α (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment (abstract). This reference teaches that the monoclonal antibody CSL362, which binds to CD123 with high affinity potently induced antibody-dependent cell cytotoxicity (ADCC) of acute myeloid lymphoma blasts including CD34+CD38−CD123+ LSCs by natural killer cells (abstract).
As such, it would have been obvious one of ordinary skill in the art at the effective filing date of the invention to have taken the method of treating cancer taught by Neville and Waller, and administered anti-CD123 antibodies because Xie teaches that it is known to treat cancer, especially leukemia, which both Waller and Neville teach are treatable through the PD-L1/PD-1 pathway. One would be motivated to do so because Xie teaches that anti-CD123 antibodies are particularly potent against leukemia, having positive clinical outcomes by inducing antibody dependent cytotoxicity. As such, there is a reasonable expectation of success that the method of Waller and Neville can be combined with CD123 antibodies to treat leukemia.
Claims 15-19 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Waller et al. (US2017/0258904) in view of Neville et al. (WO2018/031507), and in further view of Klippstein et al. (Advances in Protein Chemistry and Structural Biology; Chapter Five - Vasoactive Intestinal Peptide (VIP) Nanoparticles for Diagnostics and for Controlled and Targeted Drug Delivery Volume 98, 2015, Pages 145-168).
The teachings of Waller and Neville have been described supra.
Klippstein teaches that VIP has been identified as a bioactive agent for inflammatory, neurodegenerative, and cancer-related diseases, but the effective translation of preclinical studies related to VIP faces delivery challenges that are common to neuropeptides (abstract). This reference teaches that recent studies developing nanostructured organic and inorganic systems either for the appropriate delivery of VIP or for VIP targeting, which serve as an alternative starting point for chemical manipulations of the neuropeptides in order to improve potency, selectivity, or pharmacokinetic parameters (abstract). This reference teaches that nanoparticles exhibit a good potential for surface modification and provide an excellent pharmacokinetic control for neuropeptides, such as VIP and that studies have used VIP to show nanoparticle benefits, including high stability over broad ranges of temperature and pH, high potential for surface functionalization, and their intrinsic optical/electrical properties (p. 146). Furthermore, Klippstein teaches that nanoparticles multitask by combining different functionalities into a single stable construct, for example, incorporating a drug, a contrast agent and a targeting molecule within the same system (Fig. 1; p. 146).
It would have been obvious to one of ordinary skill in the art at the effective filing date of the invention to have taken the method of Waller and Neville and use a nanoparticle conjugated VIP because Klippstein teaches that nanoparticles have been shown to provide more effective delivery systems for VIP neuropeptides. One would be motivated to do so to improve stability, surface functionalization and optimal optical and electrical properties, especially for combining multiple functionalities within a single construct. As such, there is a reasonable expectation of success that the method of Waller and Neville can better deliver the VIP, immune checkpoint inhibitor and anti-cancer antibody when conjugated to the nanoparticle, as taught by Klippstein.
Conclusion
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654