DETAILED ACTION
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 .
Applicant’s amendment, filed on 11/20/2025, is acknowledged.
Claims 1 and 17-28 are currently pending.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 1 and 17, directed to a composition comprising an IgG degrading enzyme and an oncolytic virus, and the species of: 1) a chemotherapeutic drug; 2) PI3K inhibitor; 3) cyclophosphamide; and 4) a CTLA-4 antibody, filed on 11/20/2025, is acknowledged.
Claims 18-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Applicant elected “chemotherapeutic drug” as the elected species of additional therapeutic, and cyclophosphamide as the elected species of chemotherapeutic drug. This elected species will be examined before the search is extended to additional unelected therapeutic species.
Claims 1 and 17 are currently under examination.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 5/26/2023 and 12/09/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
Priority
Applicant’s claim for the benefit of a prior-filed Chinese Application No. 202010507997.5, filed on June 5, 2020, is acknowledged.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Specifically, the specification discloses an embedded hyperlink on pg. 2, line 8.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claim 1 uses the open language “comprises an immunoglobulin-degrading enzyme” and “having an amino acid as set forth in SEQ ID NO: X”. The phrase results in a polypeptide comprising the claimed amino acid sequence or any portion of the claimed “SEQ ID NO: X”. The claim terminology “an amino acid sequence as set forth in SEQ ID NO: X” does not place size limits on the polypeptide size, but rather reads on any portion of the claimed polypeptide sequence. The claimed immunoglobulin-degrading enzyme sequence is generic with respect to size, encompassing anything from dimers on up to the full size of the claimed SEQ ID NOs. Claim 17 does not resolve the issue and is also rejected under 35 U.S.C. 112(a) written description.
Amending claim 1 to recite “having the amino acid sequence as set forth in SEQ ID NO: 1” instead of “having an amino acid sequence as set forth in SEQ ID NO: 1”
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.
Claim 17 is 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 phrase “such as” recited in claim 17 renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Cerullo et al. (Mol Ther. 2011 Sep;19(9):1737-46. doi: 10.1038/mt.2011.113. Epub 2011 Jun 14) in view of Majhen et al. (Hum Gene Ther. 2014 Apr;25(4):301-17. doi: 10.1089/hum.2013.235. Epub 2014 Mar 31) and Leborgne et al. (Nat Med. 2020 Jul;26(7):1096-1101. doi: 10.1038/s41591-020-0911-7. Epub 2020 Jun 1, on IDS submitted 12/09/2025), as evidenced by UnitProt entry Q7DAM2 (www.uniprot.org/uniprotkb/Q7DAM2/entry, sequence version 7/5/2004).
Cerullo et al. teaches pharmaceutical compositions comprising the chemotherapeutic cyclophosphamide and the Ad5-D24-GMCSF oncolytic adenovirus serotype 5 (i.e., Adv5) to treat pancreatic cancer (Results): “Syrian hamsters bearing a syngeneic pancreatic tumor were treated with low-dose CP in combination with Ad5-D24-GMCSF, which is an p16-Rb pathway selective adenovirus with an unmodified Ad5 capsid expressing GMCSF driven by the adenoviral E3 promoter.”
Cerullo et al. further teaches that the combination therapy of the Adv5 oncolytic virus and cyclophosphamide extends survival and the clinical benefit of pancreatic cancer bearing human subjects (Fig. 5, cropped below):
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Cerullo et al. teaches that these patients still generate neutralizing antibodies to the administered oncolytic virus, even in the presence of cyclophosphamide (Fig. 2, cropped below):
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Cerullo et al. teaches: “Interestingly, our findings provide preliminary evidence that CP treatment might enhance the efficacy of oncolytic adenoviruses (Figure 5). Higher clinical benefit rates were seen in all CP groups in comparison to the virus-only control group.”
Cerullo et al. does not teach a pharmaceutical combination comprising an Adv5 oncolytic virus, cyclophosphamide, and the IdeS enzyme.
Majhen et al., in the same field of endeavor, teaches that adenoviruses are used as oncolytic viruses, including Adv5 serotypes (pg. 310-311): “[e]ven though replication-competent OAds are rapidly cleared from the bloodstream and the tumor microenvironment, they still have potential to induce innate and adaptive immunity against tumors… A recent clinical trial evaluating Ad5/3-D24-GMCSF (granulocyte macrophage colony-stimulating factor-coding AdV5 capsid chimeric adenovirus) reported first-in-human immunologic data suggesting that the induction of antiviral immunity might correlate with the induction of antitumor T cell immunity…”
Majhen et al., teaches that adenovirus such as Adv5 are highly immunogenic (pg. 304): “Adenoviruses are highly immunogenic and induce both innate and adaptive immune responses in mammalian hosts…” Majhen et al. further teaches that most individuals have preexisting adenovirus immunity (pg. 304-305): “[a]s virtually every individual will be infected by one or more adenovirus at some point in life, often at an early age, most populations display preexisting immunity to the most common adenovirus serotypes. As a consequence, the prevalence of neutralizing antibodies against AdV5 and other common serotypes is high in humans…”.
Majhen et al. additionally teaches that this immunogenicity and pre-existing immunity in subjects presents a challenge for adenovirus based therapies, including with Adv5 serotypes, prompting efforts to reduce this immunogenicity (pg. 305): “[a]ctivation of host innate immune responses and preexisting immunity to common adenovirus serotypes may limit the efficacy of adenovirus-based vaccine vectors. Adenovirus vector-specific cytotoxic T cells and neutralizing antibodies may impede the induction of immune responses to the vaccine-encoded antigens, as they may reduce the dose and duration of exposure of target cells to the vaccine antigens. These features have forced the development of new strategies to evade undesired antivector host immune responses, including the search for other types of adenoviruses that occur at low prevalence in human populations.”
Majhen et al. demonstrates that Adv5-based therapeutics, including oncolytic viruses, face a challenge in they are highly immunogenic, leading to patients mounting an immune response against the oncolytic virus, impacting efficacy of the therapeutic. Thus, Majhen et al. presents motivation to one of ordinary skill in the art to find methods to reduce the host response to administered oncolytic Adv5-based viruses, such as the ones taught in both Cerullo et al. and Majhen et al.
Leborgne et al., in the same field of endeavor, teaches that adeno-associated viruses (AAV) has the same problem as Adv5 based therapeutics in that they both elicit an immune response against the virus when administered, leading to neutralizing antibodies of the virus (pg. 1096): “…neutralizing antibodies directed against the AAV capsid pose a major limitation to AAV gene transfer…”
Leborgne et al. teaches that the IdeS can be used to enzymatically digest neutralizing antibodies against administered viruses such as AAV (pg. 1096): “[i]n this study, we explored the use of the IgG-degrading enzyme derived from Streptococcus pyogenes IdeS13 as a strategy to overcome the limitation of neutralizing antibodies to AAV…Commercially sourced (IdeS-C) or laboratory-made (IdeS) endopeptidases showed similar cleavage activity of purified human intravenous IgG (IVIg) in vitro, resulting in a complete degradation if IgG…”
Leborgne et al. concludes (pg. 1100): “[i] summary, the results presented in this article indicate that IdeS can efficiently cleave anti-AAV antibodies, thereby enhancing IgG clearance, and reducing their AAV neutralizing activity in the blood…“
It would have been obvious to one of ordinary skill in the art, to have modified the teachings of Cerullo et al. in view of Majhen et al. and Leborgne et al. to have make a pharmaceutical composition comprising cyclophosphamide, Ad5-D24-GMCSF, and IdeS with a reasonable expectation of success, as Leborgne et al. teaches that IdeS can be combined with viral-based therapies successfully to reduce the amount of neutralizing antibodies directed against the virus. One would have been motivated to make this change because Majhen et al. teaches that anti-Adv5 neutralizing antibodies present a challenge to the efficacy of therapeutics based on this virus, such as oncolytic viruses, providing motivation to find methods of reducing such host immunity. Leborgne et al. provides a potential solution in the form of administration of IdeS, which was shown to reduce neutralizing antibodies against an administered viral vector. Additionally, Cerullo et al. teaches that administration of the Adv5-based oncolytic virus leads to production of neutralizing antibodies. Thus, one would have been motivated to try to use IdeS taught by Leborgne et al. in combination with the combination of cyclophosphamide and Ad5-D24-GMCSF taught by Cerullo et al., as one with ordinary skill in the art would appreciate that IdeS could degrade host-based antibodies directed against this virus as well, potentially increasing the therapeutic efficacy.
Unitprot entry Q7DAM2, originally entered 7/5/2004, is used as an evidentiary reference to demonstrate the amino acid sequence inherent to the IdeS enzyme (i.e., the enzyme taught by Leborgne et al.). Thus, in absence of evidence to the contrary, the IdeS enzyme taught by Leborgne et al. inherently has this sequence, which is 100% identical to instant SEQ ID NO: 1, meeting this limitation in instant claim 1:
Qy 1 MRKRCYSTSAAVLAAVTLFVLSVDRGVIADSFSANQEIRYSEVTPYHVTSVWTKGVTPPA 60
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Db 1 MRKRCYSTSAAVLAAVTLFVLSVDRGVIADSFSANQEIRYSEVTPYHVTSVWTKGVTPPA 60
Qy 61 NFTQGEDVFHAPYVANQGWYDITKTFNGKDDLLCGAATAGNMLHWWFDQNKDQIKRYLEE 120
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Db 61 NFTQGEDVFHAPYVANQGWYDITKTFNGKDDLLCGAATAGNMLHWWFDQNKDQIKRYLEE 120
Qy 121 HPEKQKINFNGEQMFDVKEAIDTKNHQLDSKLFEYFKEKAFPYLSTKHLGVFPDHVIDMF 180
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Db 121 HPEKQKINFNGEQMFDVKEAIDTKNHQLDSKLFEYFKEKAFPYLSTKHLGVFPDHVIDMF 180
Qy 181 INGYRLSLTNHGPTPVKEGSKDPRGGIFDAVFTRGDQSKLLTSRHDFKEKNLKEISDLIK 240
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Db 181 INGYRLSLTNHGPTPVKEGSKDPRGGIFDAVFTRGDQSKLLTSRHDFKEKNLKEISDLIK 240
Qy 241 KELTEGKALGLSHTYANVRINHVINLWGADFDSNGNLKAIYVTDSDSNASIGMKKYFVGV 300
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Db 241 KELTEGKALGLSHTYANVRINHVINLWGADFDSNGNLKAIYVTDSDSNASIGMKKYFVGV 300
Qy 301 NSAGKVAISAKEIKEDNIGAQVLGLFTLSTGQDSWNQTN 339
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Db 301 NSAGKVAISAKEIKEDNIGAQVLGLFTLSTGQDSWNQTN 339
Regarding the limitation “wherein the pharmaceutical combination allows separate administration of the viral vector drug and agent” in claim 1, Leborgne et al. teaches that IdeS can be administered to subjects prior to viral administration, meeting this claim limitation (Fig. 2a, cropped below, see NHP5):
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Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEC JON PETERS whose telephone number is (703)756-5794. The examiner can normally be reached Monday-Friday 8:30am - 6:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MAHER M HADDAD/Primary Examiner, Art Unit 1641