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
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 8-15 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.
Claim 8 requires for the immune cell to comprise an “inactivated” VPS39 gene, but the specification does not adequately describe what structure is required for the VPS39 gene to be “inactivated”.
Without further description of the structure required for the function, one would not be able to readily envision what level of disruption of the coding sequence or mutation would meet the instant limitation of the gene being inactivated.
Instant claim 12 requires for the immune cell to comprise a “disrupted nucleic acid encoding a VPS39 polypeptide”, but the specification does not adequately describe what structure is required for the nucleic acid to be disrupted in a manner but encode a VPS39 polypeptide.
Without further description of the structure required for the function, one would not be able to readily envision what level or type of disruption would meet the instant limitation of the nucleic acid.
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 within the instant genus that have the required function as claimed. 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 1-7 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 treating melanoma comprising delivering Vps39-shRNA silenced CART cells, does not reasonably provide enablement for a method of treating any cancer via delivery of any engineered immune cell that has any level of reduction of expression of a VPS39 polypeptide. 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 claims are directed to a method of treating any cancer via delivery of any engineered immune cell that has any level of reduction of expression of a VPS39 polypeptide.
The specification demonstrates a method of treating melanoma comprising delivering Vps39-shRNA silenced CART cells.
The specification does not draw an adequate nexus between delivery of any possible engineered immune cell that has any level of reduced expression of a VPS39 polypeptide and the predictable outcome of the treatment of any possible cancer or increasing efficacy of adoptive cell transfer, which encompasses an enormous genus of cancers that have not been shown to be reliant upon VPS39 expression alone.
The specification does not draw an adequate nexus between delivery of the instant genus of constructs and the predictable outcome of treating any possible cancer, each having different etiological considerations and factors.
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 possible cancer via broad systemic delivery of any engineered immune cell having any reduction of expression of a VPS39 polypeptide 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 construct of the instant genus in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of any possible cancer. 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) 1-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Flinn et al. (Molecular Biology of the Cell, Vol. 21, 833–841, 2010), in view of Hambright et al. (Oncotarget, Vol. 6, No. 9, 2015, 7195-7208) and Simon et al. (Experimental Dermatology, 2018, 27, 1315–1321).
Flinn et al. teach: knockdown of hVps39 resulted in inhibition of insulin- and amino acid–stimulated mTORC1/S6K1 activation (abstract).
Flinn et al. teach: Blocking endosomal conversion by knockdown of a key member of the HOPS complex, hVps39, also produces merged early/late endosomes (Rink et al., 2005) and inhibits mTORC1 signaling (page 833)
Flinn et al. teach: hVps39 Knockdown HeLa cells were transfected with 140 nM Smart Pool siRNA (Dharmacon, Boulder, CO) targeting either Luciferase or hVps39, using Oligofectamine (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions (page 834).
Flinn et al. teach: We used an alternative approach to blocking early/late endosome conversion, by knocking down hVps39 in HeLa cells using a pool of four small interfering RNA (siRNA) oligonucleotides. Knockdown of hVps39 led to the formation of hybrid endosomes that were smaller than those produced by Rab5CA but still showed colocalization of EEA1 and LAMP-2 (Figure 4A). When HeLa cells were serum-starved, stimulated with insulin, and immunostained for phosphorylated ribosomal S6, the hVps39 knock down caused a near complete inhibition of insulin-stimulated S6 phosphorylation (Figure 4, B and C). Similarly, insulin-stimulated phosphorylation of S6K1 at T389 was significantly inhibited in the hVps39 knockdown cells (Figure 4, D and E). Similar to overexpression of Rab5CA, knockdown of hVps39 also led to localization of mTOR at hybrid endosomes (Figure 4F). Thus, blocking early/late endosome conversion by knockdown of hVps39 inhibits mTORC1/S6K1 signaling, suggesting that late endosomes are specifically required for mTORC1 signaling (page 836-837).
Flinn et al. teach: Thus, blocking early/late endosome conversion by knockdown of hVps39 inhibits mTORC1/S6K1 signaling, suggesting that late endosomes are specifically required for mTORC1 signaling (page 837).
Therefore, Flinn et al. teaches that knockdown of Vps39 inhibits mTORC1 signaling.
Hambright et al. teach: Given that mTORC1 controls growth and proliferation, its response to ROS would suggest that tumor cells require a chronic level of oxidative stress for their survival and metabolic demands. Since ROS can both activate and inhibit mTORC1 in a context-dependent manner, chronic oxidative stress that occurs in cancer cells is expected to stimulate growth, whereas an overload of ROS results in oxidative damage and mTORC1 inhibition, and therefore inhibits cell growth (page 7196).
Hambright et al. teach: The most pronounced effect of NexrutineR on the PI3K/AKT/mTOR signaling axis was seen by near complete inhibition of mTORC1 activity as reflected by inhibition of the phosphoforms of proteins that are immediately downstream of the mTORC1 complex including 4EBP1, p70S6K, and rpS6, which control translation and cell growth [37]. The profound inhibition of these proteins could account for the observed inhibition of cell proliferation, survival, and colony formation (page 7204).
Hambright et al. teach: Recently, Sorafenib-mediated breast cancer inhibition was shown to be dependent on mTORC1 inhibition and accompanied by mitochondrial membrane depolarization and dramatic ROS increase [42]. Further, work by Yoshida et al. suggests that mTORC1 is a redox-sensitive target with cysteine oxidants destabilizing mTOR-RAPTOR interaction but not mTOR RICTOR interaction (page 7204).
Hambright et al. teach: Given that mTORC1 controls growth and proliferation, its response to ROS in cancer cells would suggest that tumor cells require a chronic level of oxidative stress for their survival and metabolic demands
Hambright et al. teach: NexrutineR holds great promise for its ability to disrupt redox homeostasis and target the ROS/mTOR axis with particular implication for melanoma and other cancers (page 7204).
Therefore, it would have been obvious to inhibit mTORC1 to treat melanoma. It would have been obvious to inhibit mTORC1 via inhibiting VPS39 expression because Flinn et al. teaches that knockdown of Vps39 inhibits mTORC1 signaling.
It would have been obvious to deliver engineered CAR-T cells with reduced expression of VPS39 to achieve this because both CAR-T cell therapy and inhibition of MTORC1 were known to be treatment options for melanoma.
Simon et al. teaches CAR-T cell therapy in melanoma. Simon et al. teach: A commonly examined tumor model in the context of immunotherapy is melanoma, since it is known for its immunogenic features (abstract). Simon teaches that there are various clinical trials for using chimeric antigen receptors for melanoma (Table 1).
Simon et al. teach: When clinically used, the initial action of CAR- T cell therapy is the extraction of T cells from a patient’s apheresis product. After that, T cells are ex vivo genetically transduced with a CAR construct and are subsequently stimulated and expanded to obtain a high number of engineered cells before being reinfused into the patient (Figure 1) (page 1315).
Therefore, it would have been obvious to extract T cells from the melanoma patient, ex vivo genetically transduce the cells with a CAR construct and inhibit VPS39, resulting in engineered immune cells that have reduced expression of VPS39. One would do this because both inhibition of VPS39 and CART therapy were known to be treatments for melanoma due to the immunogenic features of melanoma.
It is noted that the preamble of claim 5 would necessarily flow from the method step, wherein the method step is obvious in view of the cited references. With regards to instant claim 12, it would have been obvious to inactivate VPS39 in view of the cited references, resulting in a cell that does not express an endogenous VPS39 polypeptide.
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
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