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
Acknowledgement is hereby made of receipt and entry of the communication filed on April 24, 2024. Claims 1-26 are pending and are currently examined.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
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 13-26 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 treating tumors in mice B16/F10, MC38, A9 models and peritoneal BR5 model, does not reasonably provide enablement for using a method being enabling to treat any tumor in any subject with any administrating schedules.
The base claim 13 is directed to a method of treating a tumor in a subject, the method comprising co-administering to the subject an oncolytic virotherapeutic agent and an inhibitor of tumor necrosis factor (TNF).
The instant specification discloses that the mice used for injecting oncolytic virotherapeutic agent and inhibitor of TNF is between six and eight weeks of age and the mice models are from B16/F10, MC38, A9 models and peritoneal BR5 model, and discloses that virus injection doses are different and the regime of the administration is different, for example, the instant specification discloses that viral treatment consisted of three injections (given on days 0, +2, and +4). Each injection consisted of 1 x 10^7 FFU of the indicated virus in 50 μl of sterile PBS and was delivered intratumorally into the larger of the two established tumors. Tumor area was then measured either every two days (for B16/F10 and MC38 tumors) or twice weekly (for A9 tumors) using digital calipers and is presented as tumor area determined using the formula (See [0066]) and the treatment was initiated when both tumors reached approximately 25 mm2 in area. While some experiment-to-experiment variation was observed, this was typically around day 7-9 for B16/F10 tumors and around day 14-20 for A9 tumors (See [0065]). Thus, the instant specification discloses that the subject is mice with a specific model and the administrating needs specific viral concentrations and injection time, and does not provide examples to support that the oncolytic virotherapeutic agent and an inhibitor of TNF can treat any subject with any tumor and any administering method. Accordingly, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wriqht, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(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. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
In the instant invention, the disclosure fails to provide adequate guidance pertaining to a number of these considerations as listed above:
Nature of the invention/Breadth of the claims. The base claim 13 are drawn to a method of treating a tumor in a subject, the method comprising co-administering to the subject an oncolytic virotherapeutic agent and an inhibitor of TNF. Here a generic tumor and generic subject are claimed. Also, a generic administering schedule is claimed.
State of the prior art/Predictability of the art. The concept of using the oncolytic virus and the inhibitor of the TNF to treat cancer is known in the art. The prior art reference of Fernandez teaches an enhanced system for potentiating cell-mediated oncolytic viral therapy. Also provided are modified viruses for such systems, and methods of treatment of cancers by administering such systems (See Fernandez, Abstract).
The level of one of ordinary skill/The existence of working examples. The instant working examples (See Instant specification, [0065] to [0068]) only disclose using a specific administrating schedules to treat specific mice models with specific tumors. Also, it does not disclose the oncolytic viral types with the given FFU because the FFU vary with different virus and cells. Accordingly, the invention does not provide sufficient evidence showing that any type of cancer can be treated in any subject with any administration regime.
The amount of direction provided by the inventor/ The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Based on the description above, the specification only discloses the specific treatments for specific mice models with specific tumors, and does not provide sufficient evidence showing that any tumor in any subject can be treated with any administration method as claimed.
M.P.E.P. §2164.03 [R-2] states: [I]n applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soil, 97 F.2d 623,624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488,496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). 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).
Based on the descriptions above, the specification does not provide sufficient guidance to allow one skilled in the art to practice the claimed invention on the full scope with a reasonable expectation of success and without undue experimentation. In the absence of such guidance and evidence of working examples, the specification fails to provide an enabling disclosure commensurate in scope with the claim.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 6-7, 9, 11-15, 17-18, 20 and 22-26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fernandez et al. (US 2020/0140824 A1, published on May 7, 2020, submitted in IDS filed on April 24, 2024, hereinafter, “Fernandez”).
The base claim 1 is directed to a composition comprising a virotherapeutic agent; and an inhibitor of tumor necrosis factor (TNF).
The base claim 13 is directed to a method of treating a tumor in a subject, the method comprising co-administering to the subject an oncolytic virotherapeutic agent and an inhibitor of tumor necrosis factor (TNF).
Fernandez describes an enhanced systems for potentiating cell mediated oncolytic viral therapy. Also provided are modified viruses for such systems, and methods of treatment of cancers by administering such systems (See Abstract). Fernandez teaches that a combination and composition comprises oncolytic viruses (See e.g. [0271]- [0274]) and the TNF inhibitor such as Viral TNF Receptors (vTNFRs) that are soluble, secreted decoy receptors that bind TNFa, preventing it from binding to its natural receptor, and mitigating its antiviral effects ([0400]; [0555])), and TNFa blocking antibodies (e.g., infliximab/Remicade, etanercept/Enbrel, adalimumab/Humira) and Fludarabine (See [0560]). Fernandez also teaches that in vivo activities refer to physiological responses that result following in vivo administration of a compound or virus provided herein (or of a composition or other mixture thereof). Activity, thus, encompasses resulting therapeutic effects and pharmaceutical activity of such compounds, compositions and mixtures. Activities can be observed in in vitro and/or in vivo systems designed to test or use such activities (See e.g., [0071]).
Based on the descriptions above, Fernandez teaches a composition including the oncolytic virus and the inhibitor of tumor necrosis factor (TNF), and also teaches a method of treating cancers by administering the systems to subjects in need of such treatment (See [0003]).
Regarding claims 2-4 and 14-15, Fernandez teaches the virotherapeutic agent comprises an oncolytic virus (claim 2) by stating that delivery of oncolytic viruses can be effected via direct intratumoral injection (See e.g., [0156]) and discloses that the oncolytic virus include, but are not limited to, poxvirus, adenovirus … myxoma virus, cytomegalovirus (CMV) and lentivirus. The CD235 a-/CD45-/CD34+/CD146-/CD31-), and pericytes (CD235a-/CD45-/CD34-/CD146+/CD31-) SA-ASCs and/ or pericytes and/or the AD-MSC produced by culturing such cells, can be incubated together for a period of time that is sufficient for at least one immunomodulatory or recombinant therapeutic protein to be expressed by the oncolytic virus on the surface or inside the SA-ASC, pericytes or AD MSC carrier cells to produce the CAVES systems provided herein (See [0183]). Here the description also teaches that the oncolytic viruses can be myxoma virus (claims 3 and 14) and the myxoma virus can be recombinant for expression the therapeutic protein (See claims 4 and 15).
Regarding claims 6 and 17, Fernandez teaches that Modified viruses can contain one or more heterologous nucleic acid sequences in the form of a gene expression cassette for the expression of a heterologous (See [0047]) and VSV can be genetically modified to include suicide genes, such as herpes virus thymidine kinase (TK), or to express immune-stimulatory cytokines such as IL-4, IL-12, IFNβ or costimulatory agents such as granulocyte-macrophage-colony-stimulating factor 1 (GM-CSF1), to enhance oncolytic activity (See [0315]).
Regarding claims 7 and 18, Fernandez teaches TNFα blocking antibodies (e.g.,
infliximab/Remicade, etanercept/Enbrel, adalimumab/Humira) (See [0560]).
Regarding claims 9 and 20, Fernandez teaches that Antibody also includes synthetic antibodies, recombinantly produced antibodies, multispecific antibodies
(e.g., bispecific antibodies), human antibodies, nonhuman antibodies, humanized antibodies, chimeric antibodies, and intrabodies (See [0061]).
Regarding claims 11 and 22, Fernandez teaches that the composition comprises the Viral TNF Receptors (vTNFRs) that are soluble, secreted decoy receptors that bind TNFα, preventing it from binding to its natural receptor, and mitigating its antiviral
Effects (See [0401]).
Regarding claim 12, Fernandez teaches that the cell assisted viral expression systems (CAVESs) provided herein can be standardized for treating a patient population because viral amplification and the expression of one or more virus-encoded immunomodulatory proteins and/or recombinantly expressed therapeutic genes (See [0010]), where the extracellular poxvirus immunomodulators that can be expressed by the viruses herein include the chemokine inhibitor/binding protein A41; the TNF inhibitors/binding proteins CrmB, CrmC, CrmD and CrmE; the MHC-like
TNF-alpha inhibitor TPXV 2 (See [0375]).
Regarding claim 23, Fernandez teaches that Delivery of oncolytic viruses can be effected via direct intratumoral injection (See [0155]).
Regarding claim 24, Fernandez teaches the inhibitor of TNF is administered systemically by stating that release and spread of the virus in the tumor can occur immediately upon administration, due to the prior ex vivo initiation of
viral amplification and the expression of viral-encoded immunomodulatory and/or therapeutic genes (See [0010]) and the CAVES cab be delivered or administered to a
subject locally or systemically (See e.g., [0566]), where the immunomodulatory can be the TNF inhibitors/binding proteins CrmB, CrmC, CrmD and CrmE (See [0375]).
Regarding claims 25-26, Fernandez teaches the combination (additional) therapies administered with caves with an example of additional chemotherapy or radiation therapy can be used in addition to the combination therapy provided herein (See e.g., [0553]).
Accordingly, claims 1-4, 6-7, 9, 11-15, 17-18, 20 and 22-26 are anticipated by Fernandez.
Claim Rejections - 35 USC § 103
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 5 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Fernandez et al. (US 2020/0140824 A1, published on May 7, 2020, submitted in IDS filed on April 24, 2024, hereinafter, “Fernandez”) as applied to claims 1-4, 6-7, 9, 11-15, 17-18, 20 and 22-26 above and in view of Kiefer et al. (CA3109216 A1, published on Feb. 20, 2020).
Claims 5 and 16 requires the virotherapeutic agent comprises an expression cassette encoding the soluble ectodomain of programmed cell death protein 1 (PD 1).
Relevance of Fernandez is set forth above, however, it is silent on the encoded soluble ectodomain of PD-1.
Kiefer discloses a recombinant oncolytic virus engineered to express a soluble form of an immune checkpoint protein (See Abstract), and teaches a method and composition comprising a recombinant oncolytic virus comprising one or more expression cassettes encoding (a) a soluble form of programmed cell death protein 1 (PD1 or PD-1). The soluble PD1 is provided to enhance the effects of combination therapies with anti-PD1 antibodies by reducing the inhibitory binding of the anti-PD1 antibody to the soluble PD1 (See [0011]), where the soluble form of PD-1 is an ectodomain (See [0043]).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the teachings of Kiefer and construct an expression cassette to express the soluble ectodomain of PD1. One of skill in the art would have been motivated to do so to express the soluble ectodomain of PD1 to enhance the effects of the combination cancer therapy, and there would be a reasonable expectation of success to develop such a method and composition as claimed.
Claims 8, 10, 19 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Fernandez et al. (US 2020/0140824 A1, published on May 7, 2020, submitted in IDS filed on April 24, 2024, hereinafter, “Fernandez”) as applied to claims 1-4, 6-7, 9, 11-15, 17-18, 20 and 22-26 above and in view of Chang et al. (Mol Immunol. 2007 Jul;44(15):3789-96).
Claims 8 and 19 require that the antibody is a TNF-binding antibody fragment.
Claims 10 and 21 requires the the TNF-binding antibody fragment is a Fab, a Fab', a F(ab')2, a pFc', a Fd, a single domain antibody (sdAb ), a variable fragment (Fv), a single-chain variable fragment (scFv), a disulfide-linked Fv (sdFv), a diabody, a bivalent diabody, a linear antibody, a single-chain antibody molecule, or a multispecific antibody compound.
Although Fernandez does not explicitly point out the term “TNF-binding antibody fragment’, Fernandez teaches the recitation of "antibody" (e.g., antibody directed to an antigen expressed on an immune cell population such as, for example, T cells, yo (gd) T cells, NK cells, NKT cells to be depleted or inhibited for suppression of an immune response) includes full-length antibodies and portions thereof including antibody fragments. Antibody fragments, include, but are not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, disulfide linked Fvs ( dsFv), Fd fragments, Fd' fragments, single-chain Fvs (scFv), single-chain Fabs (scFab), diabodies, anti-idiotypic (anti-Id) antibodies, or antigen-binding fragments of any of the above (See 0061]). It would be obvious that one of skilled in the art can generate an antibody fragment to bind TNF, and the result would be predictable based on Fernandez’s teaching.
Nevertheless, Chang studies a novel human scFv fragment against TNF-α from de novo design method (See Abstract), which specifically teaches that the TNF-binding antibody fragment is a scFv fragment. Chang teaches that the novel anti-TNF scFv was designed using computer-guided molecular design method. The frameworks VH5 and Vκ1 of human antibody variable region were chosen as scaffolds to display the antagonistic peptides. The novel scFv fragment displayed significantly improved activity over the domain antibody and Fc displayed peptide (See page 3790, left column, paragraph 4).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the scFv of Chang into Fernandez’s invention to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to use the scFv as the TNF’s inhibitor, and there would be a reasonable expectation of success to develop such a method and composition as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am-4:30 pm, EST.
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/RUIXUE WANG/ Examiner, Art Unit 1672
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