Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Feb. 20, 2025. Claims 48-60 are pending and currently examined.
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 53 and 60 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.
Claim 53 is directed to the method of claim 48 further comprising a second amount of a replication competent recombinant attenuated vaccinia virus with deletion of thymidine kinase encoding and expressing human Flt3L, wherein the second amount contributes to augmenting the induced or enhanced or promoted immune response; and/or the method further comprising a third amount of inactivated MVA wherein the third amount contributes to augmenting the induced or enhanced or promoted immune response.
Here, the limitations “a second amount of a replication competent recombinant attenuated vaccinia virus with deletion of thymidine kinase encoding and expressing human Flt3L” and “a third amount of inactivated MVA wherein the third amount contributes to augmenting the induced or enhanced or promoted immune response” are not clear. The base claim 48 recites a generic “recombinant modified vaccinia Ankara (MVA) virus harboring a human Fms-like tyrosine kinase 3 ligand (hFlt3L)”, which may or may not encompass a vaccinia virus with deletion of thymidine kinase. In other words, the recombinant vaccinia virus of claim 48 does not exclude a vaccinia virus with deletion of thymidine kinase. Therefore, it is not clear if claim 53 requires administration of two different recombinant viruses – one with a TK deletion and the other without a TK deletion.
To expedite examination, claim 53 is narrowly interpreted as requiring a 1st recombinant virus without a TK deletion and a 2nd recombinant virus with a TK deletion.
Claim 60 recites “a recombinant modified vaccinia Ankara virus with deletion of vaccinia virulence factor E3 (MVADE3L)”. It is not clear how the term “(MVADE3L)” is related to the “recombinant modified vaccinia Ankara virus with deletion of vaccinia virulence factor E3”. Additionally, it is not clear if the term “MVADE3L” stands for a specific virus or any MVA virus harboring an E3L deletion.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 48-50, 52-53 and 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Zurkova et al. (ONCOLOGY REPORTS 21: 1335-1343, 2009, submitted in IDS filed on Jun. 21, 2024).
These claims are directed to a method for treating a malignant solid tumor in a subject, comprising administering to the subject an effective amount of recombinant modified vaccinia Ankara (MVA) virus harboring a human Fms-like tyrosine kinase 3 ligand (hFlt3L).
Zurkova teaches construction of a recombinant vaccinia virus expressing the soluble form of hFlt3 ligand (hFlt3L). It teaches that the authors tested the hypotheses that rVACV expressing biologically active fms-like tyrosine kinase 3 ligand (Flt3L) would show higher immunogenicity than control viruses expressing only model antigen and that coexpression of Flt3L would influence anti-tumor activity of rVACV in the preventive and therapeutic arrangements of the in vivo experiment; it teaches that to determine the effects of hFlt3L on the induction of anti-tumor immunity, they generated live vaccinia viruses that express human Flt3L (hFlt3L) regulated by the early H5 or strong synthetic E/L promoter together with fusion protein SigE7LAMP, which is a highly immunogenic form of HPV E7 oncoprotein; it teaches that coexpression of Flt3L by replication-competent virus P13-FL-SigE7LAMP induced enhancement of the cellular immune response against HPV16 E7 and VACV E3 proteins as well as increased anti-tumor efficacy in both the protective and therapeutic immunization schemes. See e.g. Abstract.
Figure 1 of Zurkova shows three recombinant vaccinia viruses used in the study. Among them, P13-H5-FL-SigE7LAMP and P13-E/L-FL-SigE7LAMP express the hFlt3L gene. See below:
PNG
media_image1.png
577
1566
media_image1.png
Greyscale
Zurkova teaches that mice by immunization with rVACVs expressing hFlt3L produced significant antibody and T cell responses (see e.g. Figure 3), and that, given the significant enhancement found in the T cell response, the authors examined whether hFlt3L coexpression during immunization could also affect protection against the subsequent formation of TC-1 tumors expressing the E7 oncoprotein and whether treatment with the double recombinants could induce regression of already formed tumors. It teaches that the authors determined the effect of hFlt3L coexpression on therapeutic immunization with rVACV. Mice were injected s.c. with TC-1 cells to establish a tumor. When every mouse had a tumor, a single i.p. dose of 1x106 PFU rVACV was given. Immunization with all three recombinants inhibited tumor growth; nevertheless, the highest tumor regression (3/6) was induced by P13-E/LFL- SigE7LAMP even though the differences were not statistically significant. Also P13-H5-FL-SigE7LAMP increased the proportion of tumor-free mice (2/6) in comparison with the P13-SigE7LAMP TK- virus (1/6). See e.g. page 1340 and Fig. 4.
Accordingly, Zurkova teaches a method of treating a malignant solid tumor in a subject (i.e. the mouse TC-1 tumor model) comprising administering to the subject an effective amount of recombinant vaccinia virus harboring a human Fms-like tyrosine kinase 3 ligand (hFlt3L). It is noted that the P13-H5-FL-SigE7LAMP and P13-E/L-FL-SigE7LAMP viruses used in the study of Zurkova are based on the vaccinia virus (VV) strain Praha. See e.g. Mackova et al. (INTERNATIONAL JOURNAL OF ONCOLOGY 24: 1581-1588, 2004), which is cited as the reference 15 of Zurkova.
Zurkova further teaches that the short-time Flt3L coexpression by MVA-H5-FL-SigE7LAMP was not sufficient to enhance anti-tumor effect of immunization. See e.g. Abstract. It teaches that in the study, the enhancing effect of Flt3L was observed with replicating virus where the cytokine expression spanned several days. The authors also prepared double recombinant MVA-H5-FL-SigE7LAMP (not shown) that only insignificantly enhanced the cellular response. See Discussion. These teachings indicate that an MVA-based viral vector harboring the same hFlt3L has been constructed and studied for anti-tumor effect, even though teachings of Zurkova-2009 suggest that the anti-tumor effect was insignificant with the short-time Flt3L coexpression by MVA-H5-FL-SigE7LAMP.
It would have been prima facie obvious for one of ordinary skill in the art at the time of invention to modified the studies disclosed in Zurkova to arrive at the invention as claimed – to develop a method of treating a malignant solid tumor with a MVA-based vaccinia vector harboring hFlt3L by administering an “effective amount” of the virus vector. There is a reasonable expectation of success since Zurkova already teaches that the “insignificant” effect in tumor treatment by MVA-H5-FL-SigE7LAMP was at least partially due to the short-time Flt3L coexpression. One of skill in the art would have found it obvious to increase the time for Flt3L expression by any approach known at the time of invention (e.g., by repeated administration).
Regarding claim 53, Zurkova teaches a recombinant vaccinia construct, P13-SigE7LAMP TK-, wherein the TK- suggests that the thymidine kinase gene is deleted in this viral vector. See Figure 2 legend. One of skill in the art would have found it obvious to include the hFlt3L gene into this vaccinia virus vector to test the antitumor efficiency, either by itself or in combination with other recombinant viral vectors disclosed in Zurkova.
Regarding claims 56-57, it would be well within the purview of one of skill in the art to determine the amount and duration of the virus administration as long as benefits persist or a maximum tolerated dose is reached.
Claims 51, 54-55 and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Zurkova et al. (ONCOLOGY REPORTS 21: 1335-1343, 2009), as applied above, in view of Wong et al. (Viruses, 2010, 2: 78-106, submitted in IDS filed on Jun. 21, 2024) and/or Greiner et al. (Clinical and Experimental Immunology, 2006, 146: 344–353, submitted in IDS filed on Jun. 21, 2024).
Claim 51 further specifies that the recombinant MVA is not harboring nucleic acid encoding or expressing a tumor antigen. Claim 54 further specifies that the recombinant MVA is administered by intratumoral or intravenous injection or a simultaneous or sequential combination of intratumoral and intravenous injection. Claim 55 further specifies that the tumor is melanoma or colon carcinoma. Claims 58-59 specify that the method of claim 48 further comprises conjointly administering to the subject an immune checkpoint blocking agent or an immune checkpoint agonist effective to block immune suppressive mechanisms within the tumor.
Relevance of Zurkova is set forth above. However, it is silent on the additional limitations of claims 51, 54-55 and 58-59.
Wong reviews studies on cancer therapies with oncolytic viruses. It teaches that gene-manipulated oncolytic viruses such as Ad, herpes virus and vaccinia virus are being developed as a new class of anti-tumoral agent. Wong teaches that oncolytic viruses can be injected intratumorally (See page 85, para 2) and that selective intratumoral replication of the virus may lead to improved efficacy over non-replicating agents due to the self-perpetuating nature of the treatment with virus multiplication, lysis of the infected tumor and spread to adjacent cells (See e.g. page 82, para 1). It teaches that expression of β-defensin-2 or macrophage inflammatory protein 1α (MIP-1α) and Fms-like tyrosine kinase-3 ligand (Flt3L) has been shown to significantly enhance anti-tumoral immune responses of an oncolytic adenovirus, and that oncolytic adenovirus armed with IL-2 and 4-1BB ligand has been demonstrated anti-tumor effects in mouse model of melanoma. See e.g. page 90, para 1.
Accordingly, teachings of Wong indicate that vaccinia virus can be used as oncolytic virus in treating cancers, that cancers treated by oncolytic viruses can include various cancers including melanoma and breast cancer, that oncolytic viruses may be armed with immune modulators, such as Flt3L, IL-2 and 4-1BB ligand, and that oncolytic viruses can be injected intratumorally.
Greiner teaches that Vaccinia virus (VV) has been tested as oncolytic virus against malignant melanoma in clinical trials for more than 40 years, that the aim of the study was to examine whether viral immune evasion mechanisms might be responsible for the ineffectiveness of WR-based vaccination strategies and whether the highly attenuated strain modified virus Ankara (MVA) differs from WR with respect to its possible immunostimulatory capacity after intratumoral injection. Using in vitro experiments, the authors compared the effect of both strains on melanoma cells and on local bystander DCs. They found that both VV-strains infected melanoma cells efficiently and caused disintegration of the actin cytoskeleton, as shown by fluorescence microscopy. See e.g. Summary.
Accordingly, teachings of Greiner indicate that vaccinia virus, including MVA, have been used in the studies on the oncolytic properties in cancer treatment and that their potential application in the treatment of melanoma was contemplated and studied at the time of invention.
It would have been prima facie obvious for one of ordinary skill in the art at the time of invention to combine the teachings of Zurkova et al., Wong et al. and Greiner et al. to arrive at the invention as claimed. One would have been motivated to do so, e.g., to evaluate the introduction of the Flt3L into an oncolytic vaccinia vector in an oncolytic cancer treatment study.
Regarding claim 51, since Wong and Greiner teach that vaccinia virus is oncolytic, one of still in the art would have found it obvious to modify the recombinant virus of Zurkova by removing the tumor antigen to evaluate how inclusion of the Flt3L gene affect the oncolytic activity of the vaccinia virus. In other words, since the rMVA not harboring nucleic acid encoding or expressing a tumor antigen can be considered as the vector for the tumor antigen gene, one of skill in the art would have found it obvious to administer it to a subject in the same study the rMVA harboring the tumor antigen gene is used as a control.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 48-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10,736,962.
Although the conflicting claims are not identical, they are not patentably distinct from each other.
The difference between instant claims 48-59 and the reference claims 1-22 is that the instant claims is generic to the MVA virus vector while the reference claims require MVAE3L. Reference claims 7-17, 19 and 22, which are drawn to a method of treating a solid cancer, anticipate instant claims 48-59, while instant claims 48-59 are also unpatentable over reference claims 1-6, 18 and 20-21, which are drawn to a composition used by the method of treating cancer, based on the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc. v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims. Instant claim 60 correlated with the reference claim 20, based on the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc. v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008).
Claims 48-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11, 285,209.
Although the conflicting claims are not identical, they are not patentably distinct from each other.
The difference between instant claims 48-59 and the reference claims 1-10 is that the instant claims are generic to the MVA virus vector while the reference claims require MVAE3L, and that the reference claims do not require treating a cancer while specify a more generic limitation of “eliciting an immune response in a subject in need thereof”. Instant claim 60 specifies that a MVADE3L which is required in the reference claims 1-10. As indicated in the art rejections above, vaccinia viruses are known to be used in cancer treatment. And, because administration of a vaccinia virus-based composition to a subject inherently elicits immune response, one of skill in the art would have found it obvious to apply the method of the reference claims to a subject with cancer in need of treatment based on the teachings of Zurkova et al., Wong et al. and Greiner et al. cited in the art rejections above.
Claims 48-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,036,279.
Although the conflicting claims are not identical, they are not patentably distinct from each other.
The difference between the instant claims and the reference claims is that the instant claims are generic to the MVA virus vector while the reference claims require MVAE3L, and that the reference claims require treating a breast or prostate cancer while the instant claims are generic to a solid tumor (with claim 55 specifies melanoma or colon cancer). The MVAE3L-Flt3L of the reference claims is a species of the generic MVA-Flt3L of the instant claims. Therefore, reference claims 1-8 either anticipate the instant claims or make obvious the instant claims over the teachings of the cited prior art. See in the art rejections above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/Primary Examiner, Art Unit 1671
Prosecution Insights