DETAILED ACTION
Disposition of Claims
Claims 1-3 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250134941A1, Published 05/01/2025.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/07/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 1 and 3 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 term “glycoprotein C (gC)-deficient” in claims 1 and 3 is a relative term which renders the claim indefinite. The term “gC-deficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While ¶[0080] of the specification is defining “gC-deficient” or “deficient in gC” as a recombinant virus having a disruption in the gC gene, further in that same paragraph, it notes that “The HSV-1 genome contains two copies of the ICP0 gene and two copies of the gC gene, therefore an ICP0-deficient virus has a disruption of both copies of the ICP0 gene, and a gC-deficient virus has a disruption of both copies of the gC gene. However, it is not necessary for both copies of the ICP0 gene or the gC gene to have the same type of disruption. For example, one copy of the ICP0 (or gC) gene could be deleted (such as completely deleted), while the second copy could contain a point mutation that prevents expression of functional ICP0 (or gC) protein.” However, the gene encoding for gC (UL44) is only present once in the HSV genome, making it unclear as to how to interpret this paragraph which provides two separate, reasonable interpretations: “gC deficient” requires disruption of the single UL44/gC gene actually present in HSV-1 or “gC deficient” requires disruption of two purported gC copies as stated in ¶[0080]. Claim 3 then creates further confusion as it refers to “the gC gene” in the singular. As the specification provides confusing guidance, the metes and bounds of the claims are unclear.
For at least these reasons, claim 1 and 3 are rejected on the grounds of being indefinite.
Claims 2-3 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.
Claims 2-3 refer to “the ICP0 gene”. However, in the wild-type HSV genome, there are two copies of the ICP0 gene, so in using the definite article “the”, it is unclear as to which copy of ICP0 the applicant is referring. It is suggested that the claims be amended to clarify that the disruption, mutation, or deletions referenced in the claims happen to “at least one copy of the ICP0 gene” or the claims be amended to clearly recite that only one or both genes are altered in the manner described.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 2-3 are rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a method of treating an alternative lengthening of telomeres (ALT)-dependent cancer in a subject, comprising:
selecting a subject having an ALT-dependent cancer; and
administering to the subject a recombinant herpes simplex virus (HSV)-1 that is infected cell protein 0 (ICP0)-deficient, glycoprotein C (gC)-deficient, or both ICP0-deficient and gC-deficient, thereby treating the ALT-dependent cancer in the subject.
Claim 2 is drawn to a recombinant herpes simplex virus (HSV)-1 comprising:
a complete deletion of the infected cell protein 0 (ICP0) gene; and
a heterologous gene encoding granulocyte-macrophage colony-stimulating factor (GM-CSF).
Claim 3 is drawn to a recombinant herpes simplex virus (HSV)-1 comprising:
a complete deletion of the infected cell protein 0 (ICP0) gene;
a mutation of the glycoprotein C (gC) gene, such that the recombinant HSV-1 is gC deficient;
a partial deletion in the infected cell protein 47 (ICP47) gene; and
a heterologous gene encoding granulocyte-macrophage colony-stimulating factor (GM-CSF).
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 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Cunha et. al. (Cunha CW, et. al. PLoS One. 2015 Jul 17;10(7):e0131129.; CITED ART OF RECORD; hereafter “Cunha”), in view of Coffin (US20030091537A1; Pub. 05/15/2003, hereafter “Coffin”) and Glorioso et. al. (WO2015009952A1; Pub. 01/22/2015; hereafter “Glorioso”.)
The Prior Art
Cunha teaches the widely used recombinant HSV-1 dl1403, which is derived from strain 17 syn+(17+) and comprises 2 kb lesions in both copies of the ICP0 gene in the HSV genome (p. 2; “Materials and Methods: Cells and viruses.”) Cunha teaches derivatives of the dl1403 virus, FXE and D8, wherein FXE lacks the RING finger domain of ICP0 and wherein D8 lacks the nuclear localization signal (NLS) of ICP0 (p. 4; “gC is not detectable in cells infected with HSV-1 dl1403”). Cunha also teaches HSV-1 derivative of KOS strain, 7134, which contains the lacZ gene in place of both copies of the ICP0 gene (p. 2; “Materials and Methods: Cells and viruses.”) Cunha teaches dl1403 contains a gC frameshift resulting from a single nucleotide deletion of C186 relative to the wild type parent 17+, which results in a frameshift and a premature stop codon at nucleotide positions 356-358, and does not express wild-type gC. Cunha teaches that unlike the wild type gC polypeptide which is 511 amino acids, the predicted polypeptide encoded by the dl1403 gC gene consists of the first 62 native gC residues followed by 112 non-gC amino acids, and a S56N amino acid substitution. Cunha states that dl1403 fails to express a detectable gC protein likely due to these reasons (p. 4; “HSV-1 dl1403 contains a frameshift mutation in its gC gene”). To compensate for loss of ICP0, the viruses were grown in U2OS tumor cells (p. 2, “Materials and Methods: Cells and viruses.”)
While Cunha teaches a virus that comprises a complete deletion of both copies of ICP0 (7134) and teaches viruses that are deficient for both copies of ICP0 and are also gC deficient (dl1403, FXE, D8), Cunha fails to teach a HSV-1 that comprises full deletions of both copies of the ICP0 gene, a gC-deficient HSV-1 due to a mutation in the gC gene, a partial deletion of ICP47, and a heterologous gene encoding GM-CSF. However, the art as provided by Coffin and Glorioso provides both remaining claimed modifications, namely partial deletion of ICP47 and expression of GM-CSF, and a clear therapeutic reason for these modifications.
Coffin teaches that ICP47 should be deleted from an oncolytic HSV because ICP47 inhibits antigen presentation, particularly when immune effects are being enhanced with GM-CSF (¶[0004]; reference claim 1). Coffin teaches that GM-CSF expression in the tumor improves antitumor immune effects (¶[0004]). Coffin teaches a gene may be inactivated by deletion of one or more portions or the entire gene, that both copies preferably are inactivated when a gene is duplicated, and that such modifications are accomplished through routine homologous-recombination techniques, such as replacement of the entire ORF with lacZ or GFP genes (¶[0004-0005][0036-0038][0056-0065]).
Glorioso teaches herpes simplex virus (HSV) vectors that have deletions or inactivating mutations in the genes ICP0, ICP4, ICP22, ICP27 and ICP47 (entire document; see abstract.) Glorioso teaches wherein one or more of the ICP0, ICP4, ICP22, ICP27, and ICP47 loci of the HSV-1 genome comprises an inactivating deletion (reference claim 9). Glorioso also teaches wherein the ICP0 coding sequences are completely deleted, and in which ICP47 is disrupted by a partial deletion. Glorioso teaches deletion of the internal HSV repeat or “joint” region, which eliminates one copy of ICP0, thereby permitting manipulation of the remaining copy (¶[0060]) Glorioso further teaches derivation of the JΔNI3 vector by “clean deletion of the ICP0 coding sequence” from the remaining ICP0 loci (¶[00107]). Accordingly, the combination of the joint deletion and clean deletion of the remaining ICP0 coding sequence results in removal of the ICP0 coding sequences from the recombinant HSV-1.
Glorioso also teaches deletion of the joint together with the first 14 nucleotides of the adjacent unique-short region containing US12/ICP47. Glorioso specifically teaches that this 14-nucleotide deletion removes the ICP47 translation-initiation codon (¶[00105-00106]). Reference claim 21 of Glorioso also recites an HSV vector having an inactivating deletion of ICP0 and “a deletion of the promoter and start codon of the gene encoding ICP47.” Therefore, Glorioso teaches a partial deletion affecting the ICP47 gene and rendering normal ICP47 expression unavailable. Glorioso further teaches that the recombinant HSV vectors can comprise one or more heterologous transgene cassettes, including transgenes expressed in cancer cells or encoding agents useful for treatment of cancer (¶[0050-0058]; reference claims 23, 55-56.)
It would have been obvious to modify the dl1403-type recombinant HSV disclosed by Cunha by 1) removing the remaining ICP0 coding sequences from both copies, consistent with the known 7134 complete ICP0 replacement as taught by Cunha, the preference noted in Coffin for deletion of the entire gene, and the instruction provided by Glorioso to delete both ICP0 copies; 2) partially deleting ICP47 to prevent production of functional ICP47 and improve antigen presentation as shown by Glorioso; and 3) inserting a heterologous GM-CSF gene to enhance local and systemic antitumor immune activity as suggested by Coffin. Coffin teaches that ICP47 disruption and GM-CSF expression are complementary oncolytic-virus modifications, and further characterizes the required deletion and insertion techniques as routine in the HSV-1 art, and Glorioso teaches that the HSV vector can be engineered to carry one or more heterologous transgenes for treatment of tumors or cancers. A skilled person would therefore have had a reasonable expectation of constructing the resulting recombinant HSV-1 of instant claims 2 and 3.
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Cunha in order to generate a recombinant HSV-1 with further mutations and modifications to native genes, such as ICP0 and ICP47, and engineered to express heterologous genes, thereby generating an oncolytic virus that could be used therapeutically. One would have been motivated to do so, given the suggestion by Glorioso and Coffin that the HSV-1 could express heterologous transgenes, such as GM-CSF, which is explicitly taught by Coffin. There would have been a reasonable expectation of success, given the knowledge that the partial ICP0 mutations could be full ICP0 deletions in the HSV genome, as taught by Cunha and Glorioso, and also given the knowledge that partial deletions could alter the ICP47 expression, as taught by Glorioso. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Cunha, Coffin, and Glorioso as applied to claims 2-3 above, and further in view of Newhart et. al. (Newhart A, et. al. J Cell Sci. 2012 Nov 15;125(Pt 22):5489-501. Epub 2012 Sep 12.; hereafter “Newhart”) and
Lovejoy et. al. (Lovejoy CA, et. al. PLoS Genet. 2012;8(7):e1002772. Epub 2012 Jul 19.; hereafter “Lovejoy”.)
The Prior Art
The teachings of Cunha, Coffin, and Glorioso have been set forth supra. While Glorioso and Coffin teach the use of oHSV to treat cancers or tumors, neither alone or in combination specifically teach the use of said oHSV in ALT-dependent cancers. However, such a limitation would be obvious, given that the art teaches Newhart with respect to oHSV and ALT-dependent cancers.
Newhart teaches that oHSV deficient for ICP0 replicate as well as wild-type virus in U2OS cells, which are an ATRX-null and ALT-positive human osteosarcoma cell line (p. 5490, left col., ¶2). Newhart teaches that Daxx and ATRX participate in transcriptional repression and resistance to viral infection, while the ATRX-negative U2OS environment permits robust activation (abstract, pp. 5489-5490, ¶ bridging pages.)
Lovejoy teaches that ALT is a telomerase-independent mechanism active in human cancers, and that ATRX loss is a hallmark of ALT-positive cells (entire document; see abstract). Lovejoy teaches 19 of 22 tested ALT lines lacked ATRX, and the authors identified ATRX-associated characteristics as useful for diagnosing and developing treatments for ALT-positive cancers (entire document; see abstract; “Author Summary”; p. 12, “Discussion”.)
Newhart teaches that the ICP0-deficient HSV-1 replicates efficiently in an ATRX-null, ALT-positive human osteosarcoma line. Lovejoy teaches that ATRX loss is a frequent hallmark of ALT-positive cancers, and that these characteristics could be used to identify ALT-positive tumors for targeted treatment. Given the teachings of Cunha, Coffin, and Glorioso, which render obvious oHSV-1 deficient for ICP0, and the use of said oHSV in treatment of cancers or tumors, and given that Cunha and Glorioso teach that said oHSV replicate in U2OS cells, it would be obvious to try to use said oHSV in similar cancer cells as it can efficiently replicate in these cells but cannot replicate in other non-cancerous cells, as U2OS complement for the loss of ICP0. Given the combined teachings of Cunha, Glorioso, Coffin, Newhart, and Lovejoy, it would be obvious to try the ICP0-deficient oHSV in the treatment of ALT-positive cancers, thus rendering the limitations of instant claim 1 obvious.
It would have been obvious to one of ordinary skill in the art to use the compositions taught by Cunha, Glorioso, and Coffin therapeutically to treat ALT-positive cancers, as oHSV-1 lacking ICP0 was able to grow in U2OS cells, a cancer cell line that was ALT-positive. One would have been motivated to do so, given that Newhart teaches that oHSV deficient for ICP0 replicate as well as wild-type virus in U2OS cells, which are an ATRX-null and ALT-positive human osteosarcoma cell line. There would have been a reasonable expectation of success, given the knowledge that specific therapies for ALT-positive cancers was in development, as taught by Lovejoy. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claim 1 is rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 1 of prior U.S. Patent No. 10,821,141. This is a statutory double patenting rejection.
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.
Claims 2-3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10 and 13 of U.S. Patent No. 10,821,141. Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons set forth herein.
Regarding claim 2, reference claim 10 of the ‘141 patent recites a method of treating an ALT-dependent cancer using a recombinant HSV-1 comprising a complete deletion of the ICP0 gene and a heterologous gene encoding GM-CSF. Thus, the patented method expressly requires administration of the same recombinant HSV-1 defined by instant claim 2. While instant claim 2 differs from ‘141 claim 10 in that it is the product, and not a method as in claim 10, the difference does not provide a patentable distinction because no structural limitation distinguishes the recombinant HSV-1 of instant claim 2 from the recombinant HSV-1 of reference claim 10.
Regarding claim 3, reference claim 13 of the ‘141 patent depends from reference claim 12 and therefore recites a method of treating an ALT-dependent cancer using a recombinant HSV-1 comprising a complete deletion of the ICP0 gene, a partial deletion of the ICP47 gene, a heterologous gene encoding GM-CSF, and a genome at least 80% identical to SEQ ID NO: 16 or SEQ ID NO: 24. The ‘141 patent identifies SEQ ID NO: 24 as the genome of an HSV-1 having a complete deletion of the ICP0 gene, a partial deletion of the ICP47 gene, a mutation of the gC gene that prevents expression of functional gC, and a heterologous gene encoding GM-CSF. Reference claim 13 therefore expressly encompasses administration of a recombinant HSV-1 species having every structural and functional limitation recited in instant claim 3. While instant claim 3 is drawn to the product used in the reference claim, the differences do not render the claims patentably distinct because the instantly claimed virus is required to carry out the patented method.
Therefore, the ‘141 claims and the instant claims are not patentably distinct.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20020072119A1. Teaches dl1403 and that said virus can further encode GM-CSF. Not utilized as rejection would be redundant to those set forth supra.
Li J. A Phase I Study of Recombinant hGM-CSF Herpes Simplex Virus to Treat Cancer. OrienGene Biotechnology Ltd. ClinicalTrials.gov ID NCT01935453. Pub.2013-08-30. Study of oHSV (OrienX010; deleted for ICP34.5, ICP47, and ICP6) engineered to express GM-CSF for treatment of Melanoma. Not utilized as rejection would be redundant to those set forth supra.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached on (571) 270-3497. 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.
/RACHEL B GILL/
Primary Examiner, Art Unit 1648
Prosecution Insights