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 December 27, 2024 in response to the Office Action of June 27, 2024 is acknowledged and has been entered.
Claims 11-13, 16, 19, 20-22, 25 and 28 have been amended.
Claims 15, 23, and 24 have been cancelled.
Claims 11-14, 16-22, 25-28 are pending and under consideration.
Claim Objections
Claim 11, which is dependent on claim 20, is objected pursuant to 37 CFR 1.75(c), a claim dependent form must refer only to a claim or claims previously set forth.
MAINTAINED/MODIFIED OBJECTIONS/REJECTIONS
Specification
The use of the term MVA-BN, which is a trade name or a mark used in commerce (as evidenced by MVA-BN, downloaded from https://tmsearch.uspto.gov/summary?serial=76319426, of record), has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 11-14, 16-22, 25-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rountree (Rountree et al., WO 2015/069571, Publication Date: 2015-05-14, #1 reference in IDS of 08/24/2021) in view of Lauterbach (Lauterbach et al., WO 2014/037124 A1, Publication Date: 2014-03-13, #2 reference in IDS of 08/24/2021).
Rountree teaches that MVA was engineered for use as a viral vector for recombinant gene expression or as a recombinant vaccine ([006]).
Rountree teaches that stains of MVA having enhanced safety profiles for the development of vaccines or pharmaceuticals have been known in the arts. One such MVA strains is MVA-BN ([008]). MVA-BN is preferred for its higher safety ([078]).
Rountree teaches an MVA encoding a HER-2 antigen (MVA-BN-HER2), which shows anti-tumor efficacy in a murine model… The anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cell, and was accompanied by a decrease in the frequency of Treg cells in the lung ([012]).
Rountree teaches the tumor associated antigens can be CEA, MUC-1, PAP, PSA, and/or a HER-2 antigen. See [0035 and 0083]
Rountree teaches several immune checkpoint molecules, such as CTLA-4, PD-1, LAG-3 ([015]), and examples of antibody antagonists or agonists to these molecules ([016]-[024]).
Rountree teaches a method of treating cancer patients, using a combination of (a) a recombinant orthopoxvirus comprising a nucleic acid encoding a polypeptide of at least one tumor antigen; (b) at least one of anti-PD-1 antagonist, an anti-LAG-3 antagonist, or an anti-ICOS agonist. It is contemplated that (a) and (b) are administered as a combination ([027]).
Rountree teaches that the recombinant orthopoxvirus can be an MVA-BN ([033]).
Rountree teaches that the anti-PD-1 antagonist comprises an antibody ([034]).
Rountree teaches that the tumor antigen can be HER2 antigen ([035]).
Rountree teaches that PD-1 expression increased in the lungs, spleen, and blood on T cells after treatment with MVN-BN-HER2 (Fig. 8, Example 10).
Rountree teaches that MVA-BN-HER2 treatment and anti-PD-1 (an anti-PD-1 antibody) slow tumor growth and increase survival in a mice solid CT26-HER-2 model. The combination is better than either treatment alone (Fig. 9; Example 11). MAV-BN-HER2, anti-PD-1 and anti-LAG-3 treatment leads to complete tumor regression in mice with CT26-HER2 tumor (Figs. 12 and 13; Example 14).
Rountree teaches that MAV-BN-CV301 and anti-PD-1 slow tumor growth in a mice MC38-CEA tumor model (Fig. 17; Example 18).
Rountree teaches intravenous administration for rMVA ([089], [0155]).
Rountree teaches dosage and administration of the invention, e.g. intravenous administration ([0162], [0163]).
Rountree teaches compositions comprising the rMVA-BN and one or more antibodies, agonists, or antagonists ([0170]), which can be used to treat cancers, including breast cancer, colorectal cancer, lung cancer, gastric cancer, pancreatic cancer, prostate cancer, bladder cancer, and/or ovarian cancer ([0173], [036]).
Rountree teaches the composition and methods can additionally comprise one or more immunostimulatory molecules ([0176]). The one or more immunostimulatory molecules can be administered in the form of a vector comprising a nucleic acid encoding one or more immunostimulatory molecules ([0176]).
Rountree teaches the method of making MVA-BN-HER2 (Example 1).
Rountree teaches as set forth above. However, Rountree does not teaches the rMAV comprising a nucleic acid encoding CD40L.
Lauterbach teaches that an ideal vaccine should induce both T-cells and antibodies (i.e., both T-cell and B-cell responses ([002]).
Lauterbach teaches that a successful cancer vaccine requires the identification of specific tumor-associated antigens characteristic of particular types of cancer and the ability to break self-tolerance so that the patient’s immune system can recognize and attack cancer cells expressing the tumor-associated antigen ([003]).
Lauterbach teaches that its proven safety and good immunogenicity make MVA a prime candidate for a T and B-cell inducing vaccine vector ([005]).
Lauterbach teaches that members of tumor necrosis factor receptor/tumor necrosis factor (“TNFR/TNF”) superfamily (including CD40/CD40L) are well known for their T-cell shaping properties ([007], [065]).
Lauterbach teaches that CD40/CD40L plays central role in co-stimulating CD8+ T-cell responses. MVA encoding CD40L showed superior immunogenicity in vitro and in vivo ([008]).
Lauterbach teaches that CD40L-adjuvanted MVA can induce antigen-specific multi-functional CD8+ T-cell responses. The recombinant MVA-CD40L is a prime candidate vector for the development of therapeutic vaccines against diseases such as cancer ([008]).
Lauterbach teaches a recombinant MVA (rMVA) comprising a nucleic acid sequence encoding a CD40L and a nucleic acid sequence encoding a heterologous disease-associated antigen, which can induce increased T-cell immune responses (i.e., greater number of cytotoxic T-cells (CTLs) compared to CTLs induced by a recombinant MVA without CD40L) specific for the heterologous disease-associated antigen when administered to a human host ([009], [0119], [0122], [0135], claims 1-6), and method of use the rMVA ([017], [0148], claims 23-28). Figs. 7 and 8 show in comparison to rMVA, rMVA-CD40L immunization leads to functionally improved primary effector CD8+ T-cells.
Lauterbach teaches the disease-associated antigen is a tumor-associated antigen (TAA) ([011]). The TAA can be Brachyury, HER2 ([016], [024], [073], [075], [0136], claim 21-22, claim 32).
Lauterbach teaches that Brachyury induces an adaptive immune response, as measured by clinical response (e.g. an increase in CD4+ T-cells, CD8+ T-cells, or B-cells, an increase in Brachyury-specific cytolytic activity, a measurable reduction in tumor size, or a reduction in number of metastases) ([0102]).
Lauterbach teaches MVA expressing Brachyury and other TAAs e.g. TRICOM ([095], [0106]).
Lauterbach teaches that MVA-CD40L increase CTL responses if used during boost (Fig.14).
Lauterbach teaches the rMVA can be used for prime-boost vaccination ([095]).
Lauterbach teaches that despite MAV-BN’s high attenuation and reduced virulence, in preclinical studies MVA-BN has been shown to elicit both humoral and cellular immune responses to vaccinia and to heterologous gene products encoded by genes cloned in the MVA genome ([0113]).
Lauterbach teaches intravenous administration for the rMVA ([0156], [0159], Example 1), and multiple administrations ([0155]).
Lauterbach teaches that rMVA-CD40L immunization enhances DC activation and innate cytokine production (Example 4); induces high number of multifunctional CD8+ T-cells and faster memory differentiation (Example 5); induces higher expression of IL-2Rα and IL-7Rα on T-cells and faster proliferation (Example 7): induces IL-12p70 in mouse and human dendritic cells (Example 10).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a HER2 expressing cancer (e.g. CT26, colon cancer) with MAV-BN-HER2 and an anti-PD1 antagonist antibody as taught by Rountree, and to add additional immunostimulatory molecule in the form of a nucleic acid, also taught by Rountree, and to add Brachyury and CD40L as the additional TAA and immunostimulatory molecule in the form of a nucleic acid, because Lauterbach teaches that 1) CD40L plays central role in stimulating CD8+ T-cell responses and MV encoding CD40L showed superior immunogenicity in vitro and in vivo ([008]); 2) CD40L induces antigen-specific multifunctional CD8+ T-cell responses; 3) in rMVA, CD40L can be used together with TAA, such as HER2 to enhance DC activation, cytokine production, memory differentiation, faster proliferation of T cells (Examples 4, 5, 7, and 10); 4) Brachyury induces an adaptive immune response, as measured by clinical response (e.g. an increase in CD4+ T-cells, CD8+ T-cells, or B-cells, an increase in Brachyury-specific cytolytic activity, a measurable reduction in tumor size, or a reduction in number of metastases); 5) Brachyury and other TAAs can be expressed together in MVA, e.g. TRICOM ([095], [0106]). Based on the teachings from Rountree and Lauterbach, one of ordinary skilled in the art would have recognized that expressing Brachyury and CD40L as additional TAA and immunostimulatory molecule in the combination (e.g. NAV-BN-HER2 + anti-PD-1 antibody) taught by Rountree would enhance the therapeutic effectiveness of the combination. Since the components, CD40L, HER2 antigen, Brachyury and anti-PD-1 are well known in the arts, as evidenced by Rountree and Lauterbach, both Rountree and Lauterbach teach intravenous administration, one of the ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method/therapy. The motivation would have been to develop a more effective cancer treatment and different uses of MAV systems.
The limitations: “wherein administration of said combination to the cancer patient reduces tumor size and/or increases the survival rate of the cancer patient as compared to a non-IV administration of (a) or an administration of (b) alone” and “wherein administration of (a) and (b) to the cancer patient reduces tumor size and/or increases the survival rate of the cancer patient as compared to a non-IV administration of (a) or an administration of (b) alone”, recited by claims 11 and 20 are merely intended results of the method steps positively recited. The court noted (quoting Minton v. Nat'/ Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."' Id. Therefore, these limitations are given no weight. The effectiveness of the claimed method is expected and so the claim is obvious.
In addition, as set forth above, combination of Rountree and Lauterbach would teach the same combination with the same administration route as claimed and to treat the same cancer as claimed, thus, the method and combination therapy taught by Rountree and Lauterbach would have produced the same claimed invention.
Regarding claims 12 and 21, Rountree teaches anti-PD1 antibody BMS-936558 ([017]), which is the same as nivolumab and ONO-4538, as evidenced by title of Gettinger (Gettinger et al., Journal of Clinical Oncology, vol. 33, number 18, 2004-2012, Publication Date: 04/20/2015).
Regarding claims 13 and 22, Rountree teaches anti-PD1 antibodies described in WO 2011/041613, which are hereby incorporated by reference ([0133]). WO 2011/041613 describes anti-PD-1 antibodies CT-011 and ONO-4538 which is pidilizumab and nivolumab as acknowledged by Applicant see paragraph 3 on page 6 of the Remarks filed on December 27, 2024.
Regarding claims 17 and 26, Rountree teaches that one or more antibodies, agonists or antagonists, according to the invention and the orthopoxvirus encoding a tumor antigen are administered at the same time ([0159]).
Regarding claims 18 and 27, Rountree teaches multiple administrations of the vaccine (e.g. first vaccination and boost vaccination) ([0156]). Example 11 teaches at least two MVA-BN-HER2 administrations (on days 1 and 15) and at least two anti-PD-1 antibody administrations (on days 1 and 15) ([0202]).
Regarding claim 19 and 28, Rountree teaches compositions comprising the rMVA-BN and one or more antibodies, agonists, or antagonists ([0170]), which can be used to treat cancers, including colorectal cancer ([0173], [036]).
Response to Arguments
For the rejections under 35 U.S.C. §103, Applicant argues:
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Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, combination of Rountree and Lauterbach would teach the same combination with the same administration route as claimed and to treat the same cancer as claimed, thus, the method and combination therapy taught by Rountree and Lauterbach would have produced the same claimed invention.
Applicant further argue unexpected benefits of the combinations recited in the amended claims. First, based on the teachings from Rountree and Lauterbach, one of ordinary skilled in the art would have expected that expressing Brachyury, CD40L as additional TAA and immunostimulatory molecule in the combination (e.g. NAV-BN-HER2 + anti-PD-1 antibody) taught by Rountree would enhance the therapeutic effectiveness of the combination. Thus, the results of Examples 17 and 18 are not unexpected.
Examples 17 and 18 teach only one PD-1 antagonist antibody in combination with only two specific rMVAs: rMVA-p15e-CD40L (Figs. 21A-B) and rMVA-HER2-Twist-CD40L (Figs. 22A-B) has shown claimed activity (increased survival and tumor reduction) in only one specific mouse cancer model (colon cancer). The rMVA tested in Examples 17 and 18 are not the same as the rMVA now claimed. Thus, the results of Examples 17 and 18 is not sufficient to overcome obviousness as set forth above.
Therefore, the rejections above are 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.
Patent No. 10,973,892
Claims 11-14, 16-22, and 25-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 7-10 of U.S. Patent No. 10,973,892 (hereinafter Pat. 892, Appl. No.: 14/425,585) in view of Rountree (Rountree et al., WO 2015/069571, Publication Date: 2015-05-14, #1 reference in IDS of 08/24/2021) and Lauterbach (Lauterbach et al., WO 2014/037124 A1, Publication Date: 2014-03-13, #2 reference in IDS of 08/24/2021).
The claims of Pat. 892 teach:
1. A method of enhancing T-cell responses specific for a disease-associated antigen in a human comprising administering intravenously to the human a priming injection of a recombinant modified vaccinia virus Ankara (MVA) that is not capable of reproductive replication in the human keratinocyte cell line HaCat and that comprises:
(a) a nucleic acid sequence encoding a CD40 ligand (CD40L) and
(b) a nucleic acid sequence encoding a heterologous disease-associated antigen; wherein the intravenous administration of the recombinant MVA induces increased numbers of cytotoxic T-cells (CTLs) specific for the heterologous disease-associated antigen, and wherein the method further comprises administering to the human one or more boosting injections of the recombinant MVA.
2. The method of claim 1, wherein the intravenous administration of the recombinant MVA induces increased numbers of cytotoxic T-cells (CTLs) specific for the heterologous disease-associated antigen after said priming injection.
3. The method of claim 1, wherein the modified vaccinia virus Ankara (MVA) is MVA-BN or a derivative of MVA-BN.
4. The method of claim 1, wherein the increased T-cell response comprises greater numbers of memory T-cells specific for the heterologous disease-associated antigen.
7. The method of claim 1, wherein the disease-associated antigen is an infectious disease antigen or a tumor-associated antigen.
8. The method of claim 1, wherein the disease-associated antigen is a tumor-associated antigen.
9. The method of claim 7, wherein the tumor-associated antigen is selected from the group consisting of: …., Brachyury,…, CEA,…, HER2/neu, … PSA,….
10. The method of claim 7, wherein the tumor-associated antigen is selected from the group consisting of: carcinoembryonic antigen (“CEA”), mucin, and prostate-specific antigen (“PSA”).
The claims of Pat. 892 teach a recombinant MVA comprising a nucleic acid encoding CD40L and a nucleic acid encoding HER2 or Brachyury as set forth above. The claims of Pat. 892 do not teach the rMVA expressing both HER2 and Brachyury, or the rMVA in combination with an anti-PD-1 antibody, or intravenous administration, or administration regimens (e.g. boosting).
Rountree and Lauterbach teach as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a rMVA comprising a first nucleic acid encoding a TAA, such as HER2 and a second nucleic acid encoding CD40L, as taught by Pat. 892, and to add Brachyury and make a combination to with an antagonists or agonists of an immune checkpoint molecule (e.g. anti-PD-1 antibody), because Rountree teach that rMVA expressing HER2 antigen and anti-PD-1 antibody combination show enhanced anti-tumor activity in mice model compared to antibody or rMVA treatment alone (e.g. Example 11 of Rountree), and to use intravenous administration for the combination, Lauterbach teaches that 1) CD40L plays central role in stimulating CD8+ T-cell responses and MV encoding CD40L showed superior immunogenicity in vitro and in vivo ([008]); 2) CD40L induces antigen-specific multifunctional CD8+ T-cell responses; 3) in rMVA, CD40L can be used together with TAA, such as HER2 to enhance DC activation, cytokine production, memory differentiation, faster proliferation of T cells (Examples 4, 5, 7, and 10); 4) Brachyury induces an adaptive immune response, as measured by clinical response (e.g. an increase in CD4+ T-cells, CD8+ T-cells, or B-cells, an increase in Brachyury-specific cytolytic activity, a measurable reduction in tumor size, or a reduction in number of metastases); 5) Brachyury and other TAAs can be expressed together in MVA, e.g. TRICOM ([095], [0106]), and because both Rountree and Lauterbach teach method of intravenous administration of the composition. Based on the teachings from the claims of Pat. 892, Rountree and Lauterbach, one of ordinary skilled in the art would have recognized that adding Brachyury and anti-PD-1 antibody in the combination (e.g. NAV-BN-HER2-Brachyury-CD40L + anti-PD-1 antibody) would enhance the therapeutic effectiveness of the combination, as set forth above. Since the components, CD40L, HER2 antigen, Brachyury and anti-PD-1 are well known in the arts, as evidenced by Rountree and Lauterbach, both Rountree and Lauterbach teach intravenous administration, one of the ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method/therapy. The motivation would have been to develop a more effective cancer treatment and different uses of MAV systems.
The limitations: “wherein administration of said combination to the cancer patient reduces tumor size and/or increases the survival rate of the cancer patient as compared to a non-IV administration of (a) or an administration of (b) alone” and “wherein administration of (a) and (b) to the cancer patient reduces tumor size and/or increases the survival rate of the cancer patient as compared to a non-IV administration of (a) or an administration of (b) alone”, recited by claims 11 and 20 are merely intended results of the method steps positively recited. The court noted (quoting Minton v. Nat'/ Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."' Id. Therefore, these limitations are given no weight. The effectiveness of the claimed method is expected and so the claim is obvious.
In addition, as set forth above, combination taught by Pat. 892, Rountree and Lauterbach would teach the same combination with the same administration route as claimed and to treat the same cancer as claimed, thus, the method taught by Rountree and Lauterbach would have inherently produced the same results as claimed.
Application No. 17/295,384
Claims 11-14, 16-23, and 25-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-8, 12, 13, 15-20, 25 and 28-32 of copending Application No. 17/295,384 (hereinafter Appl. 384, US Pub. No.: 2022/0000997 A1) in view of Rountree (Rountree et al., WO 2015/069571, Publication Date: 2015-05-14, #1 reference in IDS of 08/24/2021) and Lauterbach (Lauterbach et al., WO 2014/037124 A1, Publication Date: 2014-03-13, #2 reference in IDS of 08/24/2021).
The claims of Appl. 384 teach:
4. A method of inducing an enhanced inflammatory response in a cancerous tumor of a subject, the method comprising intratumorally administering to the subject a recombinant modified Vaccinia Ankara (MVA) comprising a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA) and a second nucleic acid encoding a 4-1BBL antigen, wherein the intratumoral administration of the recombinant MVA generates an enhanced inflammatory response in the tumor as compared to an inflammatory response generated by a non-intratumoral injection of a recombinant MVA virus comprising a first and second nucleic acid encoding a heterologous tumor-associated antigen and a 4-1BBL antigen.
5. The method of claim 4, wherein the subject is human.
8. The method of claim 4, wherein the TAA is selected from the group consisting of carcinoembryonic antigen (CEA), mucin 1 cell surface associated (MUC-1), prostatic acid phosphatase (PAP), prostate specific antigen (PSA), human epidermal growth factor receptor 2 (HER-2), survivin, tyrosine related protein 1 (TRP1), tyrosine related protein 1 (TRP2), Brachyury, PRAME, FOLR1, HERV-K-env, HERV-K-gag, p15, MEL, and combinations thereof.
12. The method of claim 4, wherein the recombinant MVA further comprises a third nucleic acid encoding a CD40L antigen.
13. The method of claim 4, further comprising administering to the subject at least one immune checkpoint molecule antagonist or agonist of CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, or ICOS.
15. The method of claim 4, wherein the administration of the recombinant MVA enhances Natural Killer (NK) cell response and enhances CD8 T cell responses specific to the TAA as compared to a non-intratumoral injection of a recombinant MVA virus comprising a first and second nucleic acid encoding a TAA and a 4-1BBL antigen.
28. A method of inducing an enhanced inflammatory response in a cancerous tumor of a subject, the method comprising administering to the subject a recombinant modified Vaccinia Ankara (MVA) comprising a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA), a second nucleic acid encoding a 4-1BBL antigen, and a third nucleic acid encoding a CD40L antigen, wherein the administration of the recombinant MVA generates an enhanced inflammatory response in the tumor as compared to an inflammatory response generated by administration of a recombinant MVA, 4-1BBL antigen, and CD40L antigen by themselves.
29. The method of claim 28 comprising administering to the subject said recombinant modified Vaccinia Ankara (MVA) by intravenous administration.
31. The method of claim 28 comprising administering to the subject said recombinant modified Vaccinia Ankara (MVA) by intravenous administration and intratumoral administration.
32. The method of claim 31 wherein said intravenous administration and said intratumoral administration are at different times.
The claims of Appl. 384 teach a recombinant MVA comprising a nucleic acid encoding CD40L and a nucleic acid encoding HER2, and a combination with an antagonist of PD1, and a method of inducing an enhanced inflammatory response in a cancerous tumor using the combination, as set forth above. The claims of Appl. 384 do not explicitly a method for reducing tumor size and/or increasing survival in a cancer patient with the rMVA in combination with an anti-PD-1 antibody, or administration regimens (e.g. boosting), or method of treating cancers, or the rMVA also expressing Brachyury.
Rountree and Lauterbach teach as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a rMVA comprising a first nucleic acid encoding a TAA, such as HER2 and a second nucleic acid encoding CD40L, and at least one immune checkpoint molecule antagonist or agonist of CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, or ICOS, as taught by Appl. 384, and to add Brachyury to the MAV, to make a combination to with an antagonists or agonists of an immune checkpoint molecule (e.g. anti-PD-1 antibody), and to use the combination for reducing tumor size and/or increasing survival in a cancer patient, because Rountree teach that rMVA expressing HER2 antigen and anti-PD-1 antibody combination show enhanced anti-tumor activity in mice model compared to antibody or rMVA treatment alone (e.g. Example 11 of Rountree), and to use intravenous administration for the combination, Lauterbach teaches that 1) CD40L plays central role in stimulating CD8+ T-cell responses and MV encoding CD40L showed superior immunogenicity in vitro and in vivo ([008]); 2) CD40L induces antigen-specific multifunctional CD8+ T-cell responses; 3) in rMVA, CD40L can be used together with TAA, such as HER2 to enhance DC activation, cytokine production, memory differentiation, faster proliferation of T cells (Examples 4, 5, 7, and 10); 4) Brachyury induces an adaptive immune response, as measured by clinical response (e.g. an increase in CD4+ T-cells, CD8+ T-cells, or B-cells, an increase in Brachyury-specific cytolytic activity, a measurable reduction in tumor size, or a reduction in number of metastases); 5) Brachyury and other TAAs can be expressed together in MVA, e.g. TRICOM ([095], [0106]), and because the Appl. 384, Rountree and Lauterbach all teach method of intravenous administration of the composition. Based on the teachings from the claims of Appl. 384, Rountree and Lauterbach, one of ordinary skilled in the art would have recognized that the combination (e.g. NAV-BN-HER2-Brachyury-CD40L + anti-PD-1 antibody) would enhance the therapeutic effectiveness of the combination. Since the components, CD40L, HER2 antigen, Brachyury and anti-PD-1 are well known in the arts, as evidenced by Appl. 384, Rountree and Lauterbach, one of the ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method/therapy. The motivation would have been to develop a more effective cancer treatment and different uses of MAV systems.
The limitations: “wherein administration of said combination to the cancer patient reduces tumor size and/or increases the survival rate of the cancer patient as compared to a non-IV administration of (a) or an administration of (b) alone” and “wherein administration of (a) and (b) to the cancer patient reduces tumor size and/or increases the survival rate of the cancer patient as compared to a non-IV administration of (a) or an administration of (b) alone”, recited by claims 11 and 20 are merely intended results of the method steps positively recited. The court noted (quoting Minton v. Nat'/ Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."' Id. Therefore, these limitations are given no weight. The effectiveness of the claimed method is expected and so the claim is obvious.
This is a provisional nonstatutory double patenting rejection.
Application No. 17/778,374
Claims 11-14, 16-23, and 25-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 7-18, and 25 of copending Application No. 17/778,374 (hereinafter Appl. 374, US Pub. No.: 2023/0190922 A1) in view of Rountree (Rountree et al., WO 2015/069571, Publication Date: 2015-05-14, #1 reference in IDS of 08/24/2021) and Lauterbach (Lauterbach et al., WO 2014/037124 A1, Publication Date: 2014-03-13, #2 reference in IDS of 08/24/2021).
The claims of Appl. 374 teach:
7. A method of inducing an enhanced inflammatory response in a cancerous tumor of a subject, the method comprising intratumorally administering to the subject a recombinant modified Vaccinia Ankara (MVA) comprising a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA), a second nucleic acid encoding a 4-1BBL antigen, and a third nucleic acid encoding a CD40L antigen, wherein the intratumoral administration of the recombinant MVA generates an enhanced inflammatory response in the tumor as compared to an inflammatory response generated by a non-intratumoral injection of a recombinant MVA virus comprising a first nucleic acid encoding a heterologous tumor-associated antigen, a second nucleic acid encoding a 4-1BBL antigen, and a third nucleic acid encoding a CD40L antigen.
8. A recombinant modified Vaccinia virus Ankara (MVA) comprising:
(a) a first nucleic acid encoding a tumor-associated antigen (TAA);
(b) a second nucleic acid encoding a 4-1BB ligand (4-1BBL); and
(c) at least one further nucleic acid encoding a TAA.
9. The recombinant MVA according to claim 8, further comprising:
(d) a nucleic acid encoding a CD40 ligand (CD40L).
10. The recombinant MVA according to claim 9, comprising two, three, four, five, six, or more nucleic acids each encoding a different TAA.
11. The recombinant MVA according to claim 9, wherein the TAA is selected from the group consisting of an endogenous retroviral (ERV) protein, an endogenous retroviral (ERV) peptide, carcinoembryonic antigen (CEA), mucin 1 cell surface associated (MUC-1), prostatic acid phosphatase (PAP), prostate specific antigen (PSA), human epidermal growth factor receptor 2 (HER-2), survivin, tyrosine related protein 1 (TRP1), tyrosine related protein 1 (TRP2), Brachyury, p15, AH1A5, folate receptor alpha (FOLR1), preferentially expressed antigen of melanoma (PRAME), and MEL; and combinations thereof.
16. The recombinant MVA of claim 9 that is derived from MVA-BN.
17. A pharmaceutical preparation or composition comprising a recombinant MVA according to claim 9.
18. The pharmaceutical preparation or composition according to claim 17 which is adapted to intratumoral and/or intravenous administration, preferably intratumoral administration.
25. The method of claim 7, wherein the recombinant MVA is the MVA of claim 9.
The claims of Appl. 374 teach a recombinant MVA comprising nucleic acids encoding CD40L and a nucleic acid encoding HER2, and a combination with an antagonist of PD1, and a method of inducing an enhanced inflammatory response in a cancerous tumor using the combination as set forth above. The claims of Appl. 374 do not teach the rMVAin encoding Brachyury or combination with an anti-PD-1 antibody, or intravenous administration, or administration regimens (e.g. boosting), or method of reducing tumor size and/or increasing survival in a cancer patient.
Rountree and Lauterbach teach as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a rMVA comprising a first nucleic acid encoding a TAA, such as HER2 and a third nucleic acid encoding CD40L, as taught by Appl. 374, and to add Brachyury to rMAV and to make a combination to with an antagonists or agonists of an immune checkpoint molecule (e.g. anti-PD-1 antibody), because Rountree teach that rMVA expressing HER2 antigen and anti-PD-1 antibody combination show enhanced anti-tumor activity in mice model compared to antibody or rMVA treatment alone (e.g. Example 11 of Rountree), and to use intravenous administration for the combination, Lauterbach teaches that 1) CD40L plays central role in stimulating CD8+ T-cell responses and MV encoding CD40L showed superior immunogenicity in vitro and in vivo ([008]); 2) CD40L induces antigen-specific multifunctional CD8+ T-cell responses; 3) in rMVA, CD40L can be used together with TAA, such as HER2 to enhance DC activation, cytokine production, memory differentiation, faster proliferation of T cells (Examples 4, 5, 7, and 10); 4) Brachyury induces an adaptive immune response, as measured by clinical response (e.g. an increase in CD4+ T-cells, CD8+ T-cells, or B-cells, an increase in Brachyury-specific cytolytic activity, a measurable reduction in tumor size, or a reduction in number of metastases); 5) Brachyury and other TAAs can be expressed together in MVA, e.g. TRICOM ([095], [0106]), and because Appl. 374, Rountree and Lauterbach all teach method of intravenous administration of the composition. Based on the teachings from the claims of Appl. 374, Rountree and Lauterbach, one of ordinary skilled in the art would have recognized that adding anti-PD-1 antibody in the combination (e.g. NAV-BN-HER2-4-1BBL-CD40L + anti-PD-1 antibody) would enhance the therapeutic effectiveness of the combination and could be used for reducing tumor size and/or increasing survival in a cancer patient. Since the components, CD40L, HER2 antigen, Brachyury and anti-PD-1 are well known in the arts, as evidenced by Rountree and Lauterbach, both Rountree and Lauterbach teach intravenous administration, one of the ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method/therapy. The motivation would have been to develop a more effective cancer treatment and different uses of MAV systems.
The limitations: “wherein administration of said combination to the cancer patient reduces tumor size and/or increases the survival rate of the cancer patient as compared to a non-IV administration of (a) or an administration of (b) alone” and “wherein administration of (a) and (b) to the cancer patient reduces tumor size and/or increases the survival rate of the cancer patient as compared to a non-IV administration of (a) or an administration of (b) alone”, recited by claims 11 and 20 are merely intended results of the method steps positively recited. The court noted (quoting Minton v. Nat'/ Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."' Id. Therefore, these limitations are given no weight. The effectiveness of the claimed method is expected and so the claim is obvious.
In addition, as set forth above, combination taught by Appl. 374, Rountree and Lauterbach would teach the same combination with the same administration route as claimed and to treat the same cancer as claimed, thus, the method taught by Appl. 374, Rountree and Lauterbach would have inherently produced the same results as claimed.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For the Double Patenting rejection, Applicant argues:
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It is noted that rejections over co-pending Applications 17/227,350 is withdrawn because the application has been abandoned.
However, Applicant’s arguments for other rejections have been fully considered but they are not persuasive because the claims of the instant application are still obvious in view of the patented or co-pending claims and a terminal disclaimer has not been filed. Therefore, the rejections above are maintained for the reasons of record.
NEW GROUNDS OF REJECTIONS
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11-14 and 16-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The amended claim 11 is now drawn to administering the combination therapy of claim 20 which renders the claim indefinite because it is unclear if the method just comprises administering MVA/PD-1 antibody combination of claim 20, or also performing the steps of claim 20 in addition to the steps of claim 11.
In addition, claim 11 recites “said recombinant modified Vaccinia Ankara (MVA) virus”. It is not clear whether “said recombinant modified Vaccinia Ankara (MVA) virus” encodes CD40L. Thus, it is not clear whether the steps of claim 11 require administering CD40L.
Claim 14 recites the limitation "the TAA" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 12-13 and 16-19 are also rejected because these claims depend on claim 11.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 14 , which is dependent to claim 20, recites “wherein the TAA is selected from the group consisting of: carcinoembryonic antigen (CEA), Mucin 1, cell surface associated (MUC-1), Prostatic Acid Phosphatase (PAP), Prostate Specific Antigen (PSA), human epidermal growth factor receptor 2 (HER2), survivin, tyrosine related protein 1 (TRP1), tyrosine related protein 2 (TRP2), Brachyury antigen, AHIA5, p15e, or combinations thereof”. However, claim 20 recites “tumor-associated antigens (TAAs) selected from: (i) AH1A5, p15e, and TRP2 or (ii) HER2 and Brachyury”. Thus, claim 14 fails to further limiting claim 20.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 16 and 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are drawn to wherein the MVA is MVA-BN® or a derivative of MVA-BN® as deposited with the ECACC under number V00083008. To be enabled one of skill in the art must be able to have access to the deposited MVA-BN® upon grant of the patent.
The specification teaches that MVA-BN® was deposited in compliance with the Budapest Treat. See p. 36-[0140].
Given that deposit was made under the provisions of the Budapest Treaty, applicant must file of an affidavit or declaration by applicants, assignees, or a statement by an attorney of record over his or her signature and registration number stating that the deposits have been accepted by an International Depository Authority under the provisions of the Budapest Treaty, that all restrictions upon public access to the deposits will be irrevocably removed upon the grant of a patent on this application and that the deposit will be replaced if viable samples cannot be dispensed by the depository is required. See MPEP 2404.01 and Ex parte Hildebrand, 15 USPQ2d 1662 (Bd. Pat. App. & Int. 1990). This requirement is necessary when deposits are made under the provisions of the Budapest Treaty as the Treaty leaves these specific matters to the discretion of each State. For each deposit made pursuant to these regulations, the specification shall contain (MPEP § 1.809(d):
(1) The accession number for the deposit;
(2) The date of the deposit;
(3) A description of the deposited biological material sufficient to specifically
identify it and to permit examination; and
(4) The name and address of the depository.
Conclusion
No claims are allowed.
All other objections and rejections set forth in the previous Office Action of 06/27/2024 are hereby withdrawn in view of the amendments and Applicant’s argument.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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