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
The amendment filed February 2, 2026 in response to the Office Action of September 4, 2025 is acknowledged and has been entered.
Claims 1 and 23 have been amended.
Claim 4 has been cancelled.
Claims 1, 5-11, 13, 15-17, and 19-25 are pending and under consideration.
The 112(b) rejection set forth in the previous Office Action of September 4, 2025 is withdrawn in view of the amendments on claim 23.
The 102 rejection set forth in the previous Office Action of September 4, 2025 is withdrawn in view of the amendment on claim 1.
Information Disclosure Statement
The Information Disclosure Statement filed on 03/19/2026 has been considered and entered by examiner.
MAINTAINED/MODIFIED 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, 5-11, 13, 15-17 and 19-25 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. This is a WRITTEN DESCRIPTION rejection.
Claim 1 is directed to a method of treating a cancer, which is achieved by administering three components: (i) an oncolytic virus; (ii) a virus comprising a nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody; (iii) cells comprising CAR specific for a cancer cell antigen. Structurally, given Broadest Reasonable Interpretation (BRI), an oncolytic virus would encompass any and all oncolytic virus of any genome; a virus comprising a nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody would encompass any and all virus of any genome; cells comprising a CAR specific for a cancer cell antigen would encompass any and all types of cells of different origins including non-immune cells. Thus, the claims encompass unlimited number of combinations of the three components. Functionally, the claims require the successful treatment of a cancer of any type, including breast cancer, head and neck cancer, lung cancer, etc., as evidenced by claim 25.
Vas-Gath, Inc. v" Mahurkar, 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed".
"[A] sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can
'visualize or recognize' the members of the genus." Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutsch and GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number" of species.
The specification shows adequate written description for an improved antitumor effect in a cancer model using a specific combination of three components. Examples 4 and 6 show that the specific oncolytic adenovirus (OncAd) in combination a specific helper-dependent adenovirus (HDAd) and specific CAR-T cells. The specification fails to provide an adequate number of combinations broadly defined by the claims which would support the genus of combinations as claimed in the treatment of all cancers.
As evidenced by paragraph [0004] of the instant publication US 2022/0387530 A1, HDAd encodes packing signals, and OncAd replication machinery can act in trans to replicate and package both OncAd and HDAd within infected tumor cells. Thus, the combination of HDAd and OncAd allows multiple cycles of production and release of both the oncolytic virus and the transgenes encoded by the HDAd. The specification does not teach any other combination of oncolytic virus and virus comprising nucleic acids encoding IL-12 and antagonist anti-PD-L1 antibody which has the same property as the combination of HDAd and OncAd.
In addition, regarding “cells comprising a CAR specific for a cancer cell antigen”, given BRI, it would encompass a broad genus of cells (not only T cells). The specification discloses only T cell expressing a specific CAR (see Examples 4 and 6). One cannot extrapolate the teachings of the specification to readily visualize/recognize other types of cells encompassed by the claims because no nexus has been established between administering any cell type expressing a CAR specific for a cancer cell antigen and the treatment of cancer. It is well understood in the art that the activity of a CAR requires its expression in an immune cell, like T-cell or NK-cells, which can be directed to a tumor cell and activated by the CAR to kill the tumor cell. See Jena et al. (Blood Aug. 19, 2010 116(7): 1035-1044), entire article and pp. 1035-1037, in particular. Zabel et al. (Immunology Letters 212 (2019) pp. 53-69) teach that the basic concept of CAR therapy aims at redirecting cytotoxic lymphocytes against antigens expressed on tumor cells. To provide immune cells with ability to target new antigens, the cells are engineered to express CAR (see page 54, col. 1, para. 1). One of ordinary skill in the art would have not expected that all cells encompassed by the claim comprising a CAR encompassed by the claim would have the required properties to treat a cancer.
Furthermore, the written description provision of 35 USC § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications under the 35 USC §112 paragraph 1, "Revision 1" of Written Description Requirement (66 FR 1099-1111, March 25, 2008) state, "[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention (Id. At 1104). Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, Applicant has not shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Claims 5-11, 13, 15-17 and 19-25 also encompass the broad genus of: (i) any and all oncolytic virus of any genome; (ii) any and all virus of any genome comprising a nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody; and/or (iii) any and all types of cells of different origins comprising a CAR specific for a cancer cell antigen. Thus, these claims are also rejected.
In addition, claim 17 further recites “nucleic acid encoding an enzyme capable of catalyzing of a nontoxic factor to a cytotoxic form” which would encompass a broad genus of enzymes defined by function only. The specification disclose only one enzyme thymidine kinase in one specific setting: HDAdIL-12_TK_PD-L1. Because the enzyme is defined by function only and no structure-function relationship has been established by the specification, one of ordinary skill would not be able to readily visualize/recognize other enzyme which can be used in the claimed method. Thus, applicant failed to convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the claimed invention.
In addition, claim 22 recites: wherein the CAR comprises an antigen binding domain comprising: VL and VH sequences wherein the sequences have at least 75% sequence identity to sequences set forth by SEQ ID NOs: 16, 17, 24, 25, 32, 33, 63 and 64. Thus, as claimed, the VL and VH sequences may comprise up to 25% mismatches of identity, including substitution, deletions, insertions, or various combinations thereof at any position (including CDR regions) along the claimed sequences. By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). The specification, however, fails to support such genus of differential structures. There is no guidance is provided in preparing such sequences, in order to maintain the functional property of CAR in its specific binding to a cancer cell antigen. Thus, the specific antibody disclosed by the specification would not tell structure of other antibody variants as claimed.
Taken together, the instant specification has not provided a sufficient description for the rejected claims.
Response to Arguments
For the 112(a) Written Description rejection, Applicant argues:
The specification conveys possession of the claimed combination therapy through disclosure of common structural/functional characteristics and a representative number of species across each component. Written description does not require enumeration of every possible species to support a genus. Thus, Applicant is not required to recite a specific virus, a specific genome, or a specific cell type in the claims. Withdrawal of the written description rejection is requested.
Applicant’s arguments have been fully considered but they are not persuasive. Although written description does not require enumeration of every possible species to support a genus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number" of species. In the instant case, the claims encompass any and all oncolytic virus of any genome; a virus comprising a nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody would encompass any and all virus of any genome; cells comprising a CAR specific for a cancer cell antigen would encompass any and all types of cells of different origins including non-immune cells. Thus, the claims encompass unlimited number of combinations of the three components.
Examples 4 and 6 show that the specific oncolytic adenovirus (OncAd) in combination a specific helper-dependent adenovirus (HDAd) and specific CAR-T cells. The specification fails to provide an adequate number of combinations broadly defined by the claims which would support the genus of combinations as claimed in the treatment of all cancers. For example, the specification does not teach any other combination of oncolytic virus and virus comprising nucleic acids encoding IL-12 and antagonist anti-PD-L1 antibody which has the same property as the combination of HDAd and OncAd. In addition, one ordinary skill in the art cannot extrapolate the teachings of the specification to readily visualize/recognize other types of cells encompassed by the claims because no nexus has been established between administering any cell type expressing a CAR specific for a cancer cell antigen and the treatment of cancer.
Thus, the rejection is maintained for the reasons of record.
Claims 1, 5-11, 13, 15-17 and 19-25 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 a cancer, comprising administering to a subject:(i) an oncolytic virus and a virus comprising nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody; and (ii) cells comprising a chimeric antigen receptor (CAR) specific for a cancer cell antigen, wherein the oncolytic virus is a oncolytic adenovirus (OncAd), wherein the virus comprising nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody is a helper-dependent adenovirus (HDAd), wherein the cells comprising CAR are T cells, wherein the cancer cell antigen is HER2, and wherein the cancer is a HER2-expressing cancer,
does not reasonably provide enablement for:
a method of treating a cancer, comprising administering to a subject:(i) an oncolytic virus and a virus comprising nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody; and(ii) cells comprising a chimeric antigen receptor (CAR) specific for a cancer cell antigen.
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. This is a SCOPE OF ENABLEMENT rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
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 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).
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 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of invention and breadth of the claims:
The claims are drawn to a method of treating a cancer, comprising administering to a subject:(i) an oncolytic virus and a virus comprising nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody; and(ii) cells comprising a chimeric antigen receptor (CAR) specific for a cancer cell antigen.
The claims are broad because the claims encompass (i) a broad genus of cancers; (ii) a broad genus of oncolytic virus; (iii) a broad genus of virus comprising the nucleic acid; (iv) a broad genus of cells comprising CAR, (v) a broad genus of cancer cell antigens. Thus, the claims encompass endless combinations for treating unlimited cancers.
Relative skill in the art:
The relative skill of those in the art is high with an MD or a PhD.
Level of unpredictability in the art and State of the prior art:
Suzuki (Suzuki et al., WO 2018/195427 A2, Publication Date: October 25, 2018, cited in IDS of 05/06/2022) disclose a method comprising intratumoral administration of a combination of oncolytic adenovirus (OncAd), a HDAd expressing IL-12 + PD-L1 antagonist antibody + thymidine kinase, and followed by intravenous administration of CAR-T cells specific for HER2 (Examples 4 and 6). Suzuki showed that the combination has improved antitumor activity (Example 4 and 6, Fig. 19A-C). Thus, the prior art teaches using a combination of OncAd + HDAd_IL-12_TK_PD-L1 + HER2-CART for HER2-expressing cancer.
As set forth above, HDAd encodes packing signals, OncAd replication machinery can act in trans to replicate and package both OncAd and HDAd within infected tumor cells, thus, the combination of HDAd and OncAd allows multiple cycles of production and release of both the oncolytic virus and the transgenes encoded by the HDAd. One ordinary skill in the art could not predict that a combination of any type of oncolytic virus and any type of virus expressing IL-2 and PD-L1 antibody would achieve the same therapeutic outcome as the combination disclosed in the Examples 4 and 6.
In addition, it is well understood in the art that the activity of a CAR requires its expression in an immune cell, like T-cell or NK-cells, which can be directed to a tumor cell and activated by the CAR to kill the tumor cell. See Jena et al. (Blood Aug. 19, 2010 116(7): 1035-1044), entire article and pp. 1035-1037, in particular. Zabel et al. (Immunology Letters 212 (2019) pp. 53-69) teach that the basic concept of CAR therapy aims at redirecting cytotoxic lymphocytes against antigens expressed on tumor cells. To provide immune cells with ability to target new antigens, the cells are engineered to express CAR (see page 54, col. 1, para. 1). One of ordinary skill in the art could not predict that all cells encompassed by the claims would all have required property to treat a cancer.
Thus, one of ordinary skill in the art could not predict the outcome in cancer treatment following the administration of the endless combinations, in view of the specification and prior art.
Direction or guidance and working examples:
The working example of the specification support the combination of Onc5/3Ad2E1Δ24, HDadIL-12_TK_PD_L1 and HER2 CAR-T for an increased antitumor effect in the HER2-expressing cancer xenograft model used (Examples 4 and 6, [1060] of the instant publication US 2022/0387530 A1). However, the working examples do not support the scope of the claims, including all cancers or those of claim 25 and the broadly defined combinations of oncolytic virus, virus and cells.
The quantity of experimentation needed:
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the 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)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Given the numerous unspecified combinations and cancers encompassed by claim 1, the lack of specific guidance and the insufficient working examples, undue experimentation would be required of one of skilled in the art to produce the invention commensurate with the scope of the method as claimed.
Response to Arguments
For the 112(a) Scope of Enablement rejection, Applicant argues:
The specification teaches how to make and use the claimed invention with concrete guidance. Any variations of representative species, e.g., OncAd, HD Ad, CART cells, HER2, and HER2-expressing cancer can be contemplated and used without undue experimentation. Withdrawal of the written description rejection is requested.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above (see 112(a) Written Description rejection), the disclosed examples (e.g., OncAd, HD Ad, CART cells) do not constitute a representative number of species encompassed by the claims. The working examples do not support the scope of the claims, including all cancers or those of claim 25 and the broadly defined combinations of oncolytic virus, virus and cells. Because the claims encompass endless combinations for treating unlimited cancers, undue experimentation would be required of one of skilled in the art to produce the invention commensurate with the scope of the method as claimed.
Thus, the rejection is maintained for the reasons of record.
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, 5-11, 13, 15-17 and 19-25 are rejected under 35 U.S.C. 103 as being unpatentable over Suzuki (Suzuki et al., WO 2018/195427 A2, Publication Date: October 25, 2018, cited in IDS of 05/06/2022, of record).
Regarding claims 1, 16, 17, 19 and 20, Suzuki teaches a method of treating cancer, comprising administering to a subject: (i) an oncolytic virus; (ii) a virus comprising nucleic acid encoding an immunomodulatory factor; and (iii) at least one cell comprising a chimeric antigen receptor (CAR) specific for a cancer cell antigen (claim 1); wherein the virus comprising nucleic acid encoding an immunomodulatory factor comprises nucleic acid encoding IL-12 and/or antagonist anti-PD-L1 antibody (claim 24).
Suzuki teaches methods of: 1) making a HER2-specific CAT-T cell which can kill HER2 expressing cancer cells (Example 1); 2) making oncolytic adenovirus comprising E1A protein from adenovirus 5: Onc5/3Ad2E1Δ24, which lacks the sequence LTCHEACF (SEQ ID NO: 52) (Example 2); 3) making Helper-dependent adenovirus comprising sequence encoding expression cassettes for human IL-12, thymidine kinase, and an anti-PD-L1 antibody: HDAdIL-12_TK_PD-L1 (Example 3; § 3.1 HDAd constructs and production); 4) treating cancer in vivo with a combination of (i) an oncolytic virus + (ii) HDadIL-12_TK_PD-L1 + (iii) HER2-CAR-T (Example 4); 5) treating a cancer in vivo by injecting intratumorally a specific combination of Onc5/3Ad2E1Δ24 and HDAdIL-12_TK_PD-L1 in a ratio of 1:10, and 3 days after 1 x 106 HER2-CAR T cells are administered intravenously (Example 6, page 108, lines 21-33). It is noted that the three component combination of Example 6 in Suzuki, appears to be the same as the combination in the instant Example 6). Suzuki teaches that the combination can inhibit HER2-expressing tumor (FaDu cell-derived xenograft model) growth in vivo (Example 6; Fig. 19 A-C; page 108, lines 17-19; and page 101, lines 34-36).
Suzuki teaches the method as set forth above. However, Suzuki does not teach the dose of 1x1010, 1x1011, or 1x1012 virus particles. Suzuki also teaches that administration is preferably in a “therapeutically effective amount”, this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the condition to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners (page 37, lines 5-12). Suzuki teaches treating mice with 1x107, or 1x108 virus particles (Fig. 19A-19C; and page 109, lines 25-29). Given that the average size of mouse is about 20-30 grams and average human weight is 60-80 kg (mouse is approximately 1/2000th the wight of a human), one of ordinary skill in the art would have known to adjust the number of virus particles for treating humans and to reach the claimed doses. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 5, 6 and 8, Suzuki further teaches that 3 days after administration of the viral particles, 1 x 106 HER2-CAR T cells are administered intravenously (Example 4, page 106, lines 21-22).
Regrading claims 7 and 9, Suzuki further teaches that an oncolytic virus and HDadIL-12_TK_PD-L1 are injected intratumorally at an OncAd:HDAd ratio of 1:20 or 1:10 (Example6, page 109, lines 15-18, Fig. 19A-C).
Regarding claim 10, Suzuki teaches that an oncolytic virus and HDadIL-12_TK_PD-L1 are injected intratumorally at an OncAd:HDAd ratio of 1:20 or 1:10 (Example6, page 109, lines 15-18, Fig. 19A-C). It is noted that all the working examples in the instant application using the same ratio (1:20 or 1:10) as Suzuki. As set forth above, one of ordinary skill in the art would have known to adjust each components in the combinations to achieve the best therapeutic outcome and to reach the claimed ratio. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 11, Suzuki teaches that the oncolytic virus is an oncolytic adenovirus (OncAd) and is derived from adenovirus 5 (Ad5) (claims 11 and 12).
Regarding claim 13, Suzuki teaches that the oncolytic virus encodes an E1A protein which displays reduced binding to Rb protein as compared to E1A protein encoded by Ad5 (claim 13); wherein the E1A protein lacking the amino acid sequence LTCHEACF (claim 14).
Regarding claim 15, Suzuki teaches that the E1A protein comprises, or consists of the amino acid sequence SEQ ID NO: 34 (claim 15). As shown below, SEQ ID NO: 34 of Suzuki is the same as SEQ ID NO: 34 of the instant application:
PCT-US18-28577-34
Query Match 100.0%; Score 1535; DB 1; Length 281;
Best Local Similarity 100.0%;
Matches 281; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRHIICHGGVITEEMAASLLDQLIEEVLADNLPPPSHFEPPTLHELYDLDVTAPEDPNEE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRHIICHGGVITEEMAASLLDQLIEEVLADNLPPPSHFEPPTLHELYDLDVTAPEDPNEE 60
Qy 61 AVSQIFPESVMLAVQEGIDLFTFPPAPGSPEPPHLSRQPEQPEQRALGPVSMPNLVPEVI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AVSQIFPESVMLAVQEGIDLFTFPPAPGSPEPPHLSRQPEQPEQRALGPVSMPNLVPEVI 120
Qy 121 DPPSDDEDEEGEEFVLDYVEHPGHGCRSCHYHRRNTGDPDIMCSLCYMRTCGMFVYSPVS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DPPSDDEDEEGEEFVLDYVEHPGHGCRSCHYHRRNTGDPDIMCSLCYMRTCGMFVYSPVS 180
Qy 181 EPEPEPEPEPEPARPTRRPKLVPAILRRPTSPVSRECNSSTDSCDSGPSNTPPEIHPVVP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EPEPEPEPEPEPARPTRRPKLVPAILRRPTSPVSRECNSSTDSCDSGPSNTPPEIHPVVP 240
Qy 241 LCPIKPVAVRVGGRRQAVECIEDLLNESGQPLDLSCKRPRP 281
|||||||||||||||||||||||||||||||||||||||||
Db 241 LCPIKPVAVRVGGRRQAVECIEDLLNESGQPLDLSCKRPRP 281
Regarding claims 21 and 22, Suzuki teaches wherein the CAR comprises an antigen binding domain comprising: …; or a VL comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:32 and a VH comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:33 (claim 21). As shown below, SEQ ID NO: 32 and SEQ ID NO: 33 of Suzuki are identical to SEQ ID NO:32 and SEQ ID NO: 33 of the instant application, respectively.
SEQ ID NO: 32 alignment (LC-CRD1-3 of SEQ ID NOs: 26-27-28 (the elected species) are shaded):
CC PN WO2018195427-A2.
XX
CC PS Claim 21; SEQ ID NO 32; 166pp; English.
SQ Sequence 112 AA;
Query Match 100.0%; Score 587; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSYYPSWYQQTPGQAPRTLIYSTNTRSSGV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSYYPSWYQQTPGQAPRTLIYSTNTRSSGV 60
Qy 61 PDRFSGSILGNKAALTITGAQADDESDYYCVLYMGSGIWVFGGGTKLTVLGS 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDRFSGSILGNKAALTITGAQADDESDYYCVLYMGSGIWVFGGGTKLTVLGS 112
SEQ ID NO: 33 alignment (HC-CRD1-3 of SEQ ID NOs: 29-30-31 (the elected species) are shaded):
CC PN WO2018195427-A2.
XX
CC PS Claim 21; SEQ ID NO 33; 166pp; English.
SQ Sequence 123 AA;
Query Match 100.0%; Score 650; Length 123;
Best Local Similarity 100.0%;
Matches 123; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNY 60
Qy 61 NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGANSGGYLYGMDVWGQGTTVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGANSGGYLYGMDVWGQGTTVT 120
Qy 121 VSS 123
|||
Db 121 VSS 123
Regarding claim 23, Suzuki teaches that the method of treating a cancer comprises: (a) isolating at least one cell from a subject; (b) modifying the at least one cell to express or comprise a CAR specific for a cancer cell antigen, or a nucleic acid encoding a CAR specific for a cancer cell antigen, (c) optionally expanding the modified at least one cell, and; (d) administering the modified at least one cell to a subject (claim 27).
Regarding claim 24, Suzuki teaches that in some embodiments the cancer is a cancer expressing HER2, e.g. a cancer expressing HER2 at the cell surface (page 34, line 33-36).
Regarding claim 25, Suzuki teaches that the cancers can be a breast cancer (the last paragraph of page 35, line 32 in particular).
Response to Arguments
For the 103 rejection, Applicant argues:
To the extent Suzuki teaches murine dosing (e.g., 1x107- 1x108 particles) and general "therapeutically effective amounts," it does not disclose the specific total viral particle doses now required by claim I for the combined oncolytic and HD Ad viruses in human treatment regimens. The present amendment therefore distinguishes claim I from disclosures lacking these defined dose levels.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Suzuki teaches treating mice with 1x107, or 1x108 virus particles (Fig. 19A-19C; and page 109, lines 25-29). Given that the average size of mouse is about 20-30 grams and average human weight is 60-80 kg (mouse is approximately 1/2000th the wight of a human), one of ordinary skill in the art would have known to adjust the number of virus particles for treating humans and to reach the claimed doses. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). Thus, the rejection is maintained for the reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 10,716,818
Claims 1, 5-11, 13, 15-17 and 19-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,716,818 (hereinafter Pat. 818, corresponding Application No.: 16/430,347, cited in IDS of 09/30/2024, of record) in view of Suzuki (Suzuki et al., WO 2018/195427 A2, Publication Date: October 25, 2018, cited in IDS of 05/06/2022).
Regarding the instant claims 1, 16, 17, 19, 20 and 24, the claims of Pat. 818 teach: A method of treating a cancer, comprising administering to a subject: (i) an oncolytic adenovirus comprising a recombinant adenoviral nucleic acid comprising a nucleic sequence encoding an E1A protein that contains a deletion in its retinoblastoma (Rb) protein-binding region; (ii) a helper-dependent adenovirus comprising a recombinant adenoviral nucleic acid encoding IL-12, an antagonist anti-PD-L1 antibody, and an enzyme that catalyzes conversion of a non-toxic prodrug to an active cytotoxic form; and (iii) at least one T cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain capable of specific binding to HER2; wherein the cancer comprises cells expressing HER2. See claim 1. Thus, claim 1 of Pat. 818 teaches treating cancer comprising administering an oncolytic virus, a virus expressing IL-20 and an antagonist anti-PD-L1 antibody, and CAR-T cell which reads on the components used in the instant claim 1. In addition, claim 1 of Pat. 818 teaches: 1) a helper-dependent adenovirus which reads on the instant claim 16; 2) an enzyme capable of catalyzes conversion of a non-toxic prodrug to an active cytotoxic form which reads on the instant claim 17; 3) CAR-T cells which reads on the instant claim 19; 4) antigen binding domain capable of specific binding to HER2 which reads on the instant claim 20; 5) cancers expressing HER2 which reads on the instant claim 24.
The claims of Pat. 818 teach the method as set forth above. However, the claims of Pat. 818 do not teach the dose of 1x1010, 1x1011, or 1x1012 virus particles, the administration steps, or ratio of virus as recited by the instant claims.
Suzuki teaches as set forth above. In particular, Suzuki teaches that administration is preferably in a “therapeutically effective amount”, this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the condition to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners (page 37, lines 5-12). Suzuki teaches treating mice with 1x107, or 1x108 virus particles (Fig. 19A-19C; and page 109, lines 25-29). Given that the average size of mouse is about 20-30 grams and average human weight is 60-80 kg (mouse is approximately 1/2400th the wight of a human), one of ordinary skill in the art would have known to adjust the number of virus particles for treating humans and to reach the claimed doses. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claims 5-9, Suzuki teaches as set forth above. In particular, Suzuki teaches treating cancer in vivo by injecting intratumorally a specific combination of Onc5/3Ad2E1Δ24 and HDAdIL-12_TK_PD-L1 in a ratio of 1:10, and 3 days after 1 x 106 HER2-CAR T cells are administered intravenously (Example 6, page 108, lines 21-33). It is noted that the three component combination of Example 6 in Suzuki, appears to be the same as the combination in the instant Example 6). Suzuki teaches that the combination can inhibit tumor growth in vivo (Fig. 19 A-C).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treating a cancer, comprising administering to a subject: (i) an oncolytic adenovirus comprising a recombinant adenoviral nucleic acid comprising a nucleic sequence encoding an E1A protein that contains a deletion in its retinoblastoma (Rb) protein-binding region; (ii) a helper-dependent adenovirus comprising a recombinant adenoviral nucleic acid encoding IL-12, an antagonist anti-PD-L1 antibody, and an enzyme that catalyzes conversion of a non-toxic prodrug to an active cytotoxic form; and (iii) at least one T cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain capable of specific binding to HER2, as taught by the claims of Pat. 818, and to use the combination of Onc5/3Ad2E1Δ24 + HDAdIL-12_TK_PD-L1 + HER2-CAR T cells taught by Suzuki, because the three components taught by Suzuki read on the three components taught by the claims of Pat. 818, and the combination, dosage and administration route have been well tested and show antitumor activities in vitro and in vivo, as taught by Suzuki. One of ordinary skill in the art would have been motivated to use a widely tested administration regimens, highly effective, and available combination for treating cancers expressing HER2.
Regarding claim 10, Suzuki teaches that an oncolytic virus and HDadIL-12_TK_PD-L1 are injected intratumorally at an OncAd:HDAd ratio of 1:20 or 1:10 (Example6, page 109, lines 15-18, Fig. 19A-C). It is noted that all the examples in the instant application using the same ratio (1:20 or 1:10) as Suzuki. As set forth above, one of ordinary skill in the art would have known to adjust each components in the combinations to achieve the best therapeutic outcome and to reach the claimed ratio. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding the instant claims 11 and 13, the claims of Pat. 818 teach: the oncolytic virus encodes an E1A protein which displays reduced binding to Rb protein as compared to E1A protein encoded by Ad5. See claim 2. The deletion comprises deletion of the amino acid sequence LTCHEACF (SEQ ID NO:52). See claim 3.
Regarding the instant claim 15, the claims of Pat. 818 teach: the oncolytic virus encodes an E1A protein comprising, or consisting of, the amino acid sequence SEQ ID NO:34. See claim 4. As shown below, SEQ ID NO: 34 of Pat. 818 is the same as SEQ ID NO: 34 of the instant application:
Query Match 100.0%; Score 1535; DB 1; Length 281;
Best Local Similarity 100.0%;
Matches 281; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRHIICHGGVITEEMAASLLDQLIEEVLADNLPPPSHFEPPTLHELYDLDVTAPEDPNEE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRHIICHGGVITEEMAASLLDQLIEEVLADNLPPPSHFEPPTLHELYDLDVTAPEDPNEE 60
Qy 61 AVSQIFPESVMLAVQEGIDLFTFPPAPGSPEPPHLSRQPEQPEQRALGPVSMPNLVPEVI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AVSQIFPESVMLAVQEGIDLFTFPPAPGSPEPPHLSRQPEQPEQRALGPVSMPNLVPEVI 120
Qy 121 DPPSDDEDEEGEEFVLDYVEHPGHGCRSCHYHRRNTGDPDIMCSLCYMRTCGMFVYSPVS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DPPSDDEDEEGEEFVLDYVEHPGHGCRSCHYHRRNTGDPDIMCSLCYMRTCGMFVYSPVS 180
Qy 181 EPEPEPEPEPEPARPTRRPKLVPAILRRPTSPVSRECNSSTDSCDSGPSNTPPEIHPVVP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EPEPEPEPEPEPARPTRRPKLVPAILRRPTSPVSRECNSSTDSCDSGPSNTPPEIHPVVP 240
Qy 241 LCPIKPVAVRVGGRRQAVECIEDLLNESGQPLDLSCKRPRP 281
|||||||||||||||||||||||||||||||||||||||||
Db 241 LCPIKPVAVRVGGRRQAVECIEDLLNESGQPLDLSCKRPRP 281
Regarding the instant claim 17, the claims of Pat. 818 teach: the method according to claim 1, wherein the enzyme is selected from: thymidine kinase (the elected species), cytosine deaminase, nitroreductase, cytochrome P450, carboxypeptidase G2, purine nucleoside phosphorylase, horseradish peroxidase and carboxylesterase. See claim 7.
Regarding the instant claims 21 and 22, the claims of Pat. 818 teaches wherein the CAR comprises an antigen binding domain comprising: …; or a VL comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:32 and a VH comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:33. See claim 6. As shown below, SEQ ID NO: 32 and SEQ ID NO: 33 of Pat. 818 are identical to SEQ ID NO:32 and SEQ ID NO: 33 of the instant application, respectively.
SEQ ID NO: 32 alignment (LC-CRD1-3 of SEQ ID NOs: 26-27-28 are shaded):
US-16-430-347-32
Query Match 100.0%; Score 587; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSYYPSWYQQTPGQAPRTLIYSTNTRSSGV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSYYPSWYQQTPGQAPRTLIYSTNTRSSGV 60
Qy 61 PDRFSGSILGNKAALTITGAQADDESDYYCVLYMGSGIWVFGGGTKLTVLGS 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDRFSGSILGNKAALTITGAQADDESDYYCVLYMGSGIWVFGGGTKLTVLGS 112
SEQ ID NO: 33 alignment (HC-CRD1-3 of SEQ ID NOs: 29-30-31 are shaded):
US-16-430-347-33
Query Match 100.0%; Score 650; Length 123;
Best Local Similarity 100.0%;
Matches 123; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNY 60
Qy 61 NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGANSGGYLYGMDVWGQGTTVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGANSGGYLYGMDVWGQGTTVT 120
Qy 121 VSS 123
|||
Db 121 VSS 123
Regarding the instant claim 23, the claims of Pat. 818 teach: wherein the method of treating a cancer comprises: (a) isolating at least one cell from a subject; (b) modifying the at least one cell to express or comprise a CAR specific for a cancer cell antigen, or a nucleic acid encoding a CAR specific for a cancer cell antigen, (c) optionally expanding the modified at least one cell, and; (d) administering the modified at least one cell to a subject. See claim 9.
Regarding the instant claim 25, the claims of Pat. 818 teach: the cancer is selected from head and neck cancer, nasopharyngeal carcinoma (NPC), cervical carcinoma (CC), oropharyngeal carcinoma (OPC), gastric carcinoma (GC), hepatocellular carcinoma (HCC) and lung cancer. See claim 10.
U.S. Patent No. 11,896,634
Claims 1, 5-11, 13, 15-17 and 19-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,896,634 (hereinafter Pat. 634, corresponding Application No.: 16/607,066, of record) in view of Suzuki (Suzuki et al., WO 2018/195427 A2, Publication Date: October 25, 2018, cited in IDS of 05/06/2022, of record).
Regarding the instant claims 1, 16, 20 and 24, the claims of Pat. 634 teach: A method of treating a cancer, comprising administering to a subject: (i) an oncolytic virus; (ii) a helper dependent adenovirus (HDAd) comprising a nucleic acid encoding IL-12 and an antagonist anti-PD-L1 antibody; and (iii) at least one cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain capable of specific binding to HER2; wherein the cancer comprises cells expressing HER2. See claim 1. Thus, claim 1 of Pat. 634 teaches treating cancer comprising administering an oncolytic virus, a virus expressing IL-20 and an antagonist anti-PD-L1 antibody, and cells comprising CAR which reads on the components used in instant claim 1. In addition, claim 1 of Pat. 634 teaches: 1) a helper-dependent adenovirus which reads on the instant claim 16; 2) antigen binding domain capable of specific binding to HER2 which reads on the instant claim 20; 3) cancers expressing HER2 which reads on the instant claim 24.
The claims of Pat. 634 teach the method as set forth above. However, the claims of Pat. 634 do not teach the dose of 1x1010, 1x1011, or 1x1012 virus particles, the administration steps, or ratio of virus as recited by the instant claims.
Suzuki teaches as set forth above. In particular, Suzuki also teaches that administration is preferably in a “therapeutically effective amount”, this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the condition to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners (page 37, lines 5-12). Suzuki teaches treating mice with 1x107, or 1x108 virus particles (Fig. 19A-19C; and page 109, lines 25-29). Given that the average size of mouse is about 20-30 grams and average human weight is 60-80 kg (mouse is approximately 1/2400th the wight of a human), one of ordinary skill in the art would have known to adjust the number of virus particles for treating humans and to reach the claimed doses. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claims 5-9, Suzuki teaches as set forth above. In particular, Suzuki teaches treating cancer in vivo by injecting intratumorally a specific combination of Onc5/3Ad2E1Δ24 and HDAdIL-12_TK_PD-L1 in a ratio of 1:10, and 3 days after 1 x 106 HER2-CAR T cells are administered intravenously (Example 6, page 108, lines 21-33). It is noted that the three component combination of Example 6 in Suzuki, appears to be the same as the combination in the instant Example 6). Suzuki teaches that the combination can inhibit tumor growth in vivo (Fig. 19 A-C).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treating a cancer, comprising administering to a subject: (i) an oncolytic virus; (ii) a helper dependent adenovirus (HDAd) comprising a nucleic acid encoding IL-12 and an antagonist anti-PD-L1 antibody; and (iii) at least one cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain capable of specific binding to HER2; wherein the cancer comprises cells expressing HER2, as taught by the claims of Pat. 634, and to use the combination of Onc5/3Ad2E1Δ24 + HDAdIL-12_TK_PD-L1 + HER2-CAR T cells taught by Suzuki, because the three components taught by Suzuki read on the three components taught by the claims of Pat. 634, and the combination, dosage and administration route have been well tested and show antitumor activities in vitro and in vivo, as taught by Suzuki. One of ordinary skill in the art would have been motivated to use a widely tested administration regimens, highly effective, and available combination for treating cancers expressing HER2.
Regarding claim 10, Suzuki teaches that an oncolytic virus and HDadIL-12_TK_PD-L1 are injected intratumorally at an OncAd:HDAd ratio of 1:20 or 1:10 (Example6, page 109, lines 15-18, Fig. 19A-C). It is noted that all the examples in the instant application using the same ratio (1:20 or 1:10) as Suzuki. As set forth above, one of ordinary skill in the art would have known to adjust each components in the combinations to achieve the best therapeutic outcome and to reach the claimed ratio. In addition, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding the instant claim 11, the claims of Pat. 634 teach that the oncolytic virus is an oncolytic adenovirus (OncAd); the oncolytic virus is derived from adenovirus 5 (Ad5). See claims 2 and 3.
Regarding the instant claim 13, the claims of Pat. 634 teach the oncolytic virus encodes an E1A protein which displays reduced binding to Rb protein as compared to E1A protein encoded by Ad5; and the oncolytic virus encodes an E1A protein lacking the amino acid sequence LTCHEACF (SEQ ID NO:52). See claim 4 and 5.
Regarding the instant claim 15, the claims of Pat. 634 teach the oncolytic virus encodes an E1A protein comprising, or consisting of, the amino acid sequence SEQ ID NO:34. See claim 6. As shown below, SEQ ID NO: 34 of Pat. 634 is the same as SEQ ID NO: 34 of the instant application:
Query Match 100.0%; Score 1535; DB 1; Length 281;
Best Local Similarity 100.0%;
Matches 281; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRHIICHGGVITEEMAASLLDQLIEEVLADNLPPPSHFEPPTLHELYDLDVTAPEDPNEE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRHIICHGGVITEEMAASLLDQLIEEVLADNLPPPSHFEPPTLHELYDLDVTAPEDPNEE 60
Qy 61 AVSQIFPESVMLAVQEGIDLFTFPPAPGSPEPPHLSRQPEQPEQRALGPVSMPNLVPEVI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AVSQIFPESVMLAVQEGIDLFTFPPAPGSPEPPHLSRQPEQPEQRALGPVSMPNLVPEVI 120
Qy 121 DPPSDDEDEEGEEFVLDYVEHPGHGCRSCHYHRRNTGDPDIMCSLCYMRTCGMFVYSPVS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DPPSDDEDEEGEEFVLDYVEHPGHGCRSCHYHRRNTGDPDIMCSLCYMRTCGMFVYSPVS 180
Qy 181 EPEPEPEPEPEPARPTRRPKLVPAILRRPTSPVSRECNSSTDSCDSGPSNTPPEIHPVVP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EPEPEPEPEPEPARPTRRPKLVPAILRRPTSPVSRECNSSTDSCDSGPSNTPPEIHPVVP 240
Qy 241 LCPIKPVAVRVGGRRQAVECIEDLLNESGQPLDLSCKRPRP 281
|||||||||||||||||||||||||||||||||||||||||
Db 241 LCPIKPVAVRVGGRRQAVECIEDLLNESGQPLDLSCKRPRP 281
Regarding the instant claim 17, the claims of Pat. 634 teach that the helper dependent adenovirus comprises a nucleic acid encoding an enzyme capable of catalyzing conversion of a non-toxic factor to a cytotoxic form; wherein the enzyme is selected from: thymidine kinase, cytosine deaminase, nitro reductase, cytochrome P450, carboxypeptidase G2, purine nucleoside phosphorylase, horseradish peroxidase and carboxylesterase. See claims 10 and 11.
Regarding the instant claim 19, the claims of Pat. 634 teach that the at least one cell comprising a CAR is a T cell. See claim 7.
Regarding claims 21 and 22, the claims of Pat. 634 teaches wherein the CAR comprises an antigen binding domain comprising: …; or a VL comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:32 and a VH comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:33. See claim 9. As shown below, SEQ ID NO: 32 and SEQ ID NO: 33 of Pat. 634 are identical to SEQ ID NO:32 and SEQ ID NO: 33 of the instant application, respectively.
SEQ ID NO: 32 alignment (LC-CRD1-3 of SEQ ID NOs: 26-27-28 are shaded):
US-16-607-066-32
Query Match 100.0%; Score 587; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSYYPSWYQQTPGQAPRTLIYSTNTRSSGV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSYYPSWYQQTPGQAPRTLIYSTNTRSSGV 60
Qy 61 PDRFSGSILGNKAALTITGAQADDESDYYCVLYMGSGIWVFGGGTKLTVLGS 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDRFSGSILGNKAALTITGAQADDESDYYCVLYMGSGIWVFGGGTKLTVLGS 112
SEQ ID NO: 33 alignment (HC-CRD1-3 of SEQ ID NOs: 29-30-31 are shaded):
US-16-607-066-33
Query Match 100.0%; Score 650; Length 123;
Best Local Similarity 100.0%;
Matches 123; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNY 60
Qy 61 NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGANSGGYLYGMDVWGQGTTVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGANSGGYLYGMDVWGQGTTVT 120
Qy 121 VSS 123
|||
Db 121 VSS 123
Regarding the instant claim 23, the claims of Pat. 634 teach that the method of treating a cancer comprises: (a) isolating at least one cell from a subject; (b) modifying the at least one cell to express or comprise a CAR specific for a cancer cell antigen, or a nucleic acid encoding a CAR specific for a cancer cell antigen, wherein the CAR comprises an antigen binding domain capable of specific binding to HER2; (c) optionally expanding the modified at least one cell, and; (d) administering the modified at least one cell to a subject. See claim 12.
Regarding the instant claim 25, the claims of Pat. 634 teach that wherein the cancer is selected from head and neck cancer, nasopharyngeal carcinoma (NPC), cervical carcinoma (CC), oropharyngeal carcinoma (OPC), gastric carcinoma (GC), hepatocellular carcinoma (HCC) and lung cancer. See claim 13.
Application No. 17/287,972
Claims 1, 11, 13, 15-17 and 23-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 16, 22, 24, 46-50 of copending Application No. 17/287,972 (hereinafter Appl. 972, US 2022/0233616 A1, of record). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claims 1 and 16, the claims of Appl. 972 teach a method of treating a cancer, comprising administering to a subject: (i) a helper-dependent adenovirus (HDAd) comprising nucleic acid encoding an antigen- binding molecule comprising: (a) an antigen-binding moiety specific for an immune cell surface molecule, and (b) an antigen-binding moiety specific for a cancer cell antigen; and (ii) an oncolytic adenovirus (OncAd); wherein the HDAd additionally comprises a nucleic acid encoding IL-12 and a nucleic acid encoding an antagonist anti-PD-L1 antibody. See claim 1. Thus, HDAd reads on the virus comprising nucleic acid encoding IL-12 and antagonist anti-PD-L1 antibody and OncAd reads on the oncolytic virus of instant claim 1, respectively. Regarding the viral particle dose of 1x1010, 1x1011, or 1x1012 virus particles, it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
The claims of Appl. 972 teach the method of claim 1 further comprising administering (iii) at least one cell comprising a chimeric antigen receptor (CAR) specific for a cancer cell antigen. See claim 46. Thus, claims 1 and 46 of Appl. 972 teach the method of the instant claims 1 and 16.
Regarding instant claims 11, 13 and 15, the claims of Appl. 972 teach the OncAd is derived from adenovirus 5 (Ad5); wherein the OncAd encodes an E1A protein which displays reduced binding to Rb protein as compared to E1A protein encoded by Ad5; wherein the oncolytic virus encodes an E1A protein lacking the amino acid sequence LTCHEACF (SEO ID NO: 105); and/or wherein the OncAd encodes an ElA protein comprising the amino acid sequence SEQ ID NO:104. See claim 16. As shown below, SEQ ID NO: 104 of Appl. 972 is identical to SEQ ID NO: 34 of the instant application:
US-17-287-972A-104
Query Match 100.0%; Score 1535; DB 1; Length 281;
Best Local Similarity 100.0%;
Matches 281; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRHIICHGGVITEEMAASLLDQLIEEVLADNLPPPSHFEPPTLHELYDLDVTAPEDPNEE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRHIICHGGVITEEMAASLLDQLIEEVLADNLPPPSHFEPPTLHELYDLDVTAPEDPNEE 60
Qy 61 AVSQIFPESVMLAVQEGIDLFTFPPAPGSPEPPHLSRQPEQPEQRALGPVSMPNLVPEVI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AVSQIFPESVMLAVQEGIDLFTFPPAPGSPEPPHLSRQPEQPEQRALGPVSMPNLVPEVI 120
Qy 121 DPPSDDEDEEGEEFVLDYVEHPGHGCRSCHYHRRNTGDPDIMCSLCYMRTCGMFVYSPVS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DPPSDDEDEEGEEFVLDYVEHPGHGCRSCHYHRRNTGDPDIMCSLCYMRTCGMFVYSPVS 180
Qy 181 EPEPEPEPEPEPARPTRRPKLVPAILRRPTSPVSRECNSSTDSCDSGPSNTPPEIHPVVP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EPEPEPEPEPEPARPTRRPKLVPAILRRPTSPVSRECNSSTDSCDSGPSNTPPEIHPVVP 240
Qy 241 LCPIKPVAVRVGGRRQAVECIEDLLNESGQPLDLSCKRPRP 281
|||||||||||||||||||||||||||||||||||||||||
Db 241 LCPIKPVAVRVGGRRQAVECIEDLLNESGQPLDLSCKRPRP 281
Regarding instant claim 17, the claims of Appl. 972 teach the HDAd comprising nucleic acid encoding an antigen-binding molecule comprises nucleic acid encoding an enzyme capable of catalyzing conversion of a nontoxic factor to a cytotoxic form, and wherein the enzyme is selected from: thymidine kinase, cytosine deaminase, nitro reductase, cytochrome P450, carboxypeptidase G2, purine nucleoside phosphorylase, horseradish peroxidase and carboxylesterase. See claim 11.
Regarding instant claim 23, the claims of Appl. 972 teach that the method of treating a cancer comprises: (a) isolating at least one cell from the subject; (b) modifying the at least one cell to express or comprise a CAR specific for a cancer cell antigen, or a nucleic acid encoding a CAR specific for a cancer cell antigen; (c) optionally expanding the modified at least one cell, and; (d) administering the modified at least one cell to the subject. See claim 22.
Regarding instant claims 24 and 25, the claims of Appl. 972 teach that the cancer is selected from head and neck cancer, head and neck squamous cell carcinoma (HNSCC), nasopharyngeal carcinoma (NPC), oropharyngeal carcinoma (OPC), prostate carcinoma, pancreatic carcinoma, cervical carcinoma (CC), gastric carcinoma (GC), hepatocellular carcinoma (HCC), osteosarcoma (OS), ovarian cancer, colorectal cancer, breast cancer, HER2-positive breast cancer and lung cancer. See claim 24.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
For the Double Patenting rejection over Pat. 818 and Pat. 634, Applicant argues:
The present narrowing amendment distinguishes amended claim 1 from the claims of U.S. Pat. No. 10,716,818 and U.S. Pat. No. 11,896,634, which do not recite the specific combined total viral particle doses now required. Applicant respectfully requests reconsideration of the nonstatutory double patenting rejections against claim 1 in light of the newly added dosing limitation.
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reiterating the arguments set forth above. Thus for the reasons set forth above the rejection is maintained.
For rejection over Appl. No. 17/287,972, Applicant argues:
Applicant proposes that if, at the time the claims of the present application are determined to include allowable subject matter, a double patenting rejection is proper, a terminal disclaimer be filed at that time.
Applicant’s arguments have been fully considered but they are not persuasive. Since a terminal disclaimer has not been filed, the rejection is maintained for the reasons of record.
Conclusion
No claims are 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 CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
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