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 .
Status of Claims
Claims 1-10 are pending and under examination.
MAINTAINED REJECTIONS
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 1-10 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 claim recites a recombinant oncolytic adenovirus comprising: an interleukin-12 (IL-12) gene, a small hairpin RNA (shRNA) gene which is complementary to VEGF mRNA, having a promoter to drive the expression of IL-12 gene and shRNA against VEGF. The breadth of the claim encompasses any shRNA of VEGF.
[0058] of the specification described manufacture of shVEGF complementary DNA using primers SEQ ID NO: 4 and SEQ ID NO: 5. “The PCR product was digested with BamHI/HindIII, and cloned in a BamHI/HindIII-treated pSP72 E3/CMV-poly A adenovirus E3 shuttle vector [29], thereby manufacturing a pSP72 E3/shVEGF E3 shuttle vector.” The specification does not allude to any specific sequence or sequences of VEGF shRNAs that was used in tumor suppression. It is known that complementarity region of shRNAs are between 19-27 bases long. (See evidence in Moore, PTO-892, p. 2, last para). The specification taught that shVEGF complementary DNA comprising nucleotides 53-982 “ were used for designing shRNA, which gives a 929 bp DNA for design of shRNA. Assuming 19-27 bp shRNA, this gives:
929
-
27
-
1
=
903
to
929
-
19
-
1
=
911
different shRNAs for VEGF, which have no support in the specification.
It is submitted that the specification does not show support for any and all VEGF shRNA that can be used in the oncolytic recombinant virus composition. As such, it is submitted that the claimed subject matter was not adequately described in the specification. Claims 2-10 inherit the rejection due to their dependency on the rejected claim.
Response to Arguments: Applicants argued that a person of ordinary skill in the art, given the VEGF mRNA target disclosed in the specification, can envision the species within the genus without requiring Applicant to list every single nucleotide combination. Applicants’ arguments are unpersuasive and the specification fails to disclose the full scope of the claimed invention. It is reiterated that the specification does not provide adequate representative species structural detail or working examples demonstrating possession of the full breadth of combined elements within the claimed viral backbone. Written description requires more than disclosure of isolated components. Although the specification discloses IL-12 and shRNA for VEGF in broad terms it fails to disclose any specific shRNA sequence targeting VEGF or any representative embodiment of it integrated in the claimed adenoviral backbone lacking E1B region. “An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.” “For some biomolecules, examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession.” Here, disclosure of the general concepts of IL-12 expression and VEGF-suppression, without structural detail or sequence-level support for the claimed construct does not demonstrate possession of specific genetic combination recited in claim 1.
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.
Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Leitner et al (Clin Cancer Res. 2009 Mar 1; hereinafter "Leitner;" previously cited) in view of Chinnasamy et al (Clin Cancer Res. 2012 Mar 15; hereinafter "Chinnasamy;" previously cited).
Regarding claims 1 and 4: Leitner was directed to use of adenoviral mutants with E1B19K gene deletion for treatment of cancer with or without gemcitabine (an oncodrug). Leitner demonstrated that “ΔE1B19K-deleted mutants synergized with gemcitabine to selectively kill cultured pancreatic cancer cells and xenografts in vivo with no effect in normal cells. The corresponding wild-type virus (Ad5) stimulated drug-induced cell killing to a lesser degree.” (See Leitner Abstract). Leitner demonstrated that “Synergistic cell death occurred through enhancement of gemcitabine-induced apoptosis in the presence of both AdΔE1B19K and dl337 mutants, shown by increased cell membrane fragmentation, caspase-3 activation, and mitochondrial dysfunction.” (See Leitner Abstract; Fig. 6A).
As such prior art taught an oncovirus comprising an E1A region and inactivated E1B 19 region and an active E1B 55 region in combination with oncodrug (gemcitabine) to result in enhanced tumor killing. It is noted that Leitner did not teach an oncovirus comprising IL12 gene and a shRNA complementary to VEGF.
Chinnasamy was directed to delivering the proinflammatory cytokine interleukin (IL)-12 into tumor using T cells genetically engineered to express a chimeric antigen receptor (CAR) against the VEGF receptor-2 (VEGFR-2) for tumor suppression. (See Chinnasamy Abstract). Chinnasamy indicated that “T cells transduced with either anti–VEGFR-2 CAR or single-chain IL-12 alone did not alter the tumor growth indicating that both of them had to be expressed in the same cell to mediate tumor regression. Anti–VEGFR-2 CAR and IL-12–cotransduced T cells infiltrated the tumors, expanded, and persisted for prolonged periods.” (See Chinnasamy Abstract). As evidenced by National Cancer Institute (See PTO-892), the definition of synergy is when “two or more drugs when their combined effect is greater than the sum of the effects seen when each drug is given alone.” As such Chinnasamy taught synergistic ability of anti-VEGFR2 CAR in combination with IL12 in suppressing cancer. (See Chinnasamy Fig. 3). A person of ordinary skill in the art would have been motivated to integrate the IL-12 and VEGF suppressive functions into Leitner’s adenoviral constructs to combine their complementary mechanisms and would have reasonably expected the resulting virus to exhibit increased anti-tumor potency. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
It was known that functionally inhibiting VEGF and providing IL12 resulted in enhanced tumor potency. Further it was known that an oncolytic virus having inactivated E1B 19 was better at tumor suppression in combination with other therapeutics. As such it would have been obvious to use a shRNA against VEGF and IL12 gene in an oncolytic virus having inactivated E1B 19 in view of teachings of the art.
Claims 2 and 5, are rejected under 35 U.S.C. 103 as being unpatentable over Leitner et al (Clin Cancer Res. 2009 Mar 1; hereinafter "Leitner;" previously cited) in view of Chinnasamy et al (Clin Cancer Res. 2012 Mar 15; hereinafter "Chinnasamy;" previously cited), further in view of Chowdhury et al (Roy-Chowdhury, Jayanta et al.; Molecular Therapy; Published 2001; Hereinafter "Chowdhury;" previously cited).
Regarding claims 2 and 5: The teachings of Leitner and Chinnasamy are set forth above. Leitner and Chinnasamy do not teach insertion of a heterologous gene in E1 and E3 loci. However, Chowdhury teaches that “Cloning foreign genes into E1 and E3 deleted “first-generation” vectors accommodated foreign DNAs up to 8.3 kb.” (See Chowdhury p. 341, col. 1, 2nd paragraph). As such, Chowdhury makes it clear that it was common and well-known at the time of the invention to insert a heterologous nucleic acid into E1 and E3 loci. It is submitted that it would have been obvious for a person of ordinary skill in the art to arrive at the claimed composition in view of the disclosures of Chowdhury. As disclosed by Chowdhury, these were common and routine in the field of gene delivery or gene therapy.
Claims 3 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Leitner et al (Clin Cancer Res. 2009 Mar 1; hereinafter "Leitner;" previously cited) in view of Chinnasamy et al (Clin Cancer Res. 2012 Mar 15; hereinafter "Chinnasamy;" previously cited), further in view of Zhang et al (WO2015095249A1; Published June 25, 2016; Hereinafter "Zhang"; previously cited).
Regarding claims 3 and 6: The teachings of Leitner and Chinnasamy are set forth above. However, Leitner and Chinnasamy do not teach an IL12 construct comprising a p35, IRES and p40.
Zhang teaches an IL-12 construct with p35-IRES-p40. (See Zhang [0257]). Zhang also teaches that bicistronic vectors containing the p40 and p35 subunits separated by an IRES (internal ribosome entry site) sequence to allow independent expression of both subunits from a single vector. (See Zhang [0005]). As indicated above it is not clear from the wording of the claim if the Applicant intends each of these domains to be sequential. It is noted that Zhang also teaches an IL-12 construct comprising p40-IRES-p35. Zhang notes that bicistronic vectors containing the p40 and p35 subunits separated by an IRES (internal ribosome entry site) sequence to allow independent expression of both subunits from a single vector. (See Zhang [0005]).
A person of ordinary skill, in reading Zhang, would have recognized the desirability of expression of both subunits of IL-12 to enable efficient heterodimerization. As Zhang teaches, p35-IRES-p40 and p40-IRES-p35 are the only two orientations known to be useful for promoting IL-12 production. Thus, it would have been obvious to a person of ordinary skill in the art to try p35-IRES-p40 as the particular orientation of IL-12 to provide efficient expression of the cytokine. It has been held that "a person with ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." See KSR International Co. v Teleflex, Inc. 82 USPQ2d 1385 at 1390.
Claims 8 - 10 are rejected under 35 U.S.C. 103 as being unpatentable over Leitner et al (Clin Cancer Res. 2009 Mar 1; hereinafter "Leitner;" previously cited) in view of Chinnasamy et al (Clin Cancer Res. 2012 Mar 15; hereinafter "Chinnasamy;" previously cited) further in view of Choi et al (Gene Ther.; Published Jul. 2012; Hereinafter “Choi”; previously cited) and Zhang et al (WO2015095249A1; Published June 25, 2016; Hereinafter "Zhang"; previously cited).
Regarding claims 8-9: The teachings of Leitner and Chinnasamy are set forth above. However, Leitner and Chinnasamy do not teach treatment of thymic atrophy using the claimed oncolytic adenovirus. Choi teaches that treatment with adenovirus comprising IL-12 can treat thymic atrophy in tumor-bearing mice (See Choi Figure 8b). It is also noted that Choi teaches insertion of genes (IL-12 and GM-CSF into E1 and E3 loci (See Choi p. 712, last paragraph, col. 1), as required by claim 9.
As such a person of ordinary skill in the art would have expected to alleviate the tumor-induced thymic atrophy, when treating the tumor with an oncolytic virus comprising IL-12, as taught by Choi. The person would also have been motivated to expect alleviation in tumor-induced thymic atrophy by administering the adenovirus comprising IL-12. The person would also be motivated to insert the genes into E1 and E3 as taught by Choi.
It is also submitted that a person of ordinary skill in the art would have been motivated to combine the teachings of Leitner, Chinnasamy and Choi as each of these references are directed to cancer therapeutics.
Regarding claim 10: The teachings of Leitner, Chinnasamy and Choi are set forth above. However, Leitner, Chinnasamy and Choi in combination do not teach an IL12 construct comprising a p35, IRES and p40.
As indicated above, Zhang teaches an IL-12 construct with p35-IRES-p40. (See Zhang [0257]). Zhang also teaches that bicistronic vectors containing the p40 and p35 subunits separated by an IRES (internal ribosome entry site) sequence to allow independent expression of both subunits from a single vector. (See Zhang [0005]). As indicated above it is not clear from the wording of the claim if the Applicant intends each of these domains to be sequential. It is noted that Zhang also teaches an IL-12 construct comprising p40-IRES-p35. Zhang notes that bicistronic vectors containing the p40 and p35 subunits separated by an IRES (internal ribosome entry site) sequence to allow independent expression of both subunits from a single vector. (See Zhang [0005]).
A person of ordinary skill, in reading Zhang and Choi would have recognized the desirability of expression of both subunits of IL-12 to enable efficient heterodimerization. As Zhang teaches, p35-IRES-p40 and p40-IRES-p35 are the only two orientations known to be useful for promoting IL-12 production. Thus, it would have been obvious to a person of ordinary skill in the art to try p35-IRES-p40 as the particular orientation of IL-12 to provide efficient expression of the cytokine. It has been held that "a person with ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." See KSR International Co. v Teleflex, Inc. 82 USPQ2d 1385 at 1390.
Response to Arguments: Applicants argued that Chinnasamy is a non-analogous art as it utilizes Anti-VEGFR-2 CAR-T cells (Adoptive Cell Transfer) which is a completely different therapeutic modality from the claimed oncolytic adenovirus - T-cells are "living drugs" that infiltrate, expand, and persist in the tumor microenvironment, whereas oncolytic viruses function via infection, replication, and lysis. Applicants argued that success or synergy in a T-cell platform does not provide a reasonable expectation of success in a viral vector platform due to the vastly different pharmacokinetics and immunological mechanisms involved.
Applicants’ arguments are not persuasive. It is submitted that both cited references and the claimed invention relate to enhancement of anti-tumor efficacy through IL-12 and VEGF pathway modulation. The shared therapeutics objective, which is improving cancer treatment via immune stimulation and VEGF axis inhibition renders the references reasonable pertinent, even if delivery platforms differ. As such Chinnasamy is considered proper analogous art.
Next, Applicant argued the difference between using CART cells in Chinnasamy versus oncolytic virus therapy in the instant claims, the mechanisms of which are fundamentally different. It is submitted that the proper inquiry under § 103 is whether the prior art would have provided motivation to combine and a reasonable expectation of success. It is pointed out that “obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g.,In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).” See MPEP 2144.06 II A 4(e). It is submitted that a person of ordinary skill in the art would have reasonably expected that combining these known anti-cancer mechanisms within a gene therapy platform would enhance therapeutic efficacy.
Applicant argued that the Office incorrectly generalizes these distinct mechanisms as simply "VEGF pathway inhibition," ignoring that the specific means (CAR vs. shRNA) and targets (Receptor vs. mRNA) operate differently. According to the Applicant, there is no suggestion in Chinnasamy to replace a CAR-based surface targeting strategy with an intracellular gene-silencing strategy within a viral vector. Again, Applicants arguments are not persuasive.
It is submitted that Chinnasamy explicitly taught targeting the VEGF signaling axis to enhance anti-tumor efficacy by disrupting tumor vasculature. For example, Chinnasamy taught “[w]e have thus taken an alternate approach to ACT immunotherapy by genetically engineering lymphocytes to destroy tumor vasculature using a chimeric antigen receptor (CAR) specific for VEGF receptor-2 (VEGFR-2) overexpressed on tumor vasculature. Because most solid tumors depend on blood supply for growth, survival, and metastasis, this approach could potentially overcome problems common to targeting specific cancer antigens such as intratumor heterogeneity of antigen expression and genetic instability leading to downregulation of antigen/MHC molecules.“ (See Chinnasamy p. 2, para 2). It is submitted that the reference demonstrates that interfering with the VEGF pathway through genetic engineering of immune cells produces measurable tumor inhibition. That Chinnasamy does not merely disclose a specific CAR construct; it discloses the broader therapeutic principle that VEGF axis modulation improves anti-cancer outcomes. Applicants further pointed out that “[t]here is no suggestion in Chinnasamy to replace a CAR-based surface targeting strategy with an intracellular gene-silencing strategy within a viral vector.” It is pointed out that “[a]n express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” (See MPEP 2144.06 II). It is therefore submitted that differences in molecular target (VEGFR vs VEGF) and delivery system (CAR-T vs viral vector) do not negate the clear motivation to combine not the reasonable expectation that VEGF pathway suppression in combination with IL12 expression would improve anti-tumor outcomes.
Applicant’s assertion that the prior art fails to provide motivation to combine and the claimed invention demonstrates unexpected synergy is not persuasive. As discussed in the Office action, Leitner taught an oncolytic adenoviral platform with an inactivated E1B region that exhibits enhanced anti-tumor activity in combination with additional therapeutics, thereby providing clear rationale for incorporating further anti-cancer functional elements into the viral vector. Chinnasamy further taught that coordinated IL12 expression and VEGF axis targeting produce enhanced tumor suppression, demonstrating that these mechanisms operate cooperatively to improve anti-tumor efficacy. A person of ordinary skill in the art would have been motivated to integrate IL-12 and VEGF suppression into a known oncolytic adenoviral construct to enhance therapeutic potency, with a reasonably expectation of success. Applicant’s 37 C.F.R 1.143 declaration is unpersuasive because it does not overcome the strong teachings of prior art, which already disclose enhanced anti-tumor efficacy from combination of IL-12 and VEGF-pathway modulation, and therefore does not establish results that are truly unexpected relative to the scope and teachings of the cited prior art.
As such the obviousness rejection is maintained.
Conclusion
No claim is free of art.
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633