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 .
Restriction
The previous Examiner required a Restriction in the Office Action mailed out on 11 September 2025. Examiner identified two groups: Group 1, claims 1-8 and 14-15, drawn to an adenovirus DNA binding protein comprising a mutation in the motif of (NH)-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH, which inhibits adenovirus DNA replication in a cell; and Group 2, claims 10-13, drawn to a method of administering the protein of Group 1 to a subject.
In their Response filed on 10 November 2025, Applicant elected Group 1 without traverse.
Response to Amendment
Applicant’s Amendment filed on 10 November 2025 has been received and entered. Claims 1-8 and 10-15 were pending. Claim 12 was amended. Claims 9 and 16 were cancelled. No new claims have been added. Claims 10-13 are withdrawn from consideration as being drawn to a non-elected invention as noted in Applicant’s response on 10 November 2025 to the Restriction Requirement mailed out on 11 September 2025.
Accordingly, Claims 1-8 and 14-15 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2023/0302123 A1, Published 28 September 2023. Applicant’s amended Specifications as presented on 29 March 2023 and 30 January 2023 are acknowledged and entered.
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.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement (IDS) submitted on 10 November 2025 has been considered by the examiner. Any individual references with strikethroughs, however, have not been considered. The IDS was already considered by the previous Examiner, but it has now been considered again by the current Examiner.
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 - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Claim 1 as well as throughout the Specification. Every instance of 72-Pro-Ser-Thr-Ser-77; 350-Ser-Gly-Lys-Ser-355; NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH (all equivalents in the different Adenovirus types listed in Paragraph 0014); NH2-Ser-Gly-Lys-Ser-COOH; NH2-Ser-Gly-Lys-Ala-COOH; 31-Pro-Ser-Pro-Ser-36; 72-Pro-Ser-Thr-Ser-77; 118-Val-Gly-Phe-Ser-123; 175-Pro-Iso-Val-Ser-180; and Pro-Ser-Thr-Ser throughout the entirety of the disclosure must have a unique sequence identifier (SEQ ID NO) for every unique sequence present. These instances occur in Claim 1 as well as Paragraphs 0012, 0014-0022, 0024, 0027, and 0069-0070. Additionally, the primer sequences present in Paragraphs 0054 and 0057-0058 also require SEQ ID NOs.
All of these sequences contain at least 4 specifically defined and enumerated amino acid residues or at least 10 specifically defined and enumerated nucleotide bases and therefore each of these unique sequences must have their own unique SEQ ID NO. Please note that in Paragraph 0069 the sequences X-Gly-X-Ser and Pro/Ala-X-X-Ser do NOT require SEQ ID NOs because they have less than 4 specifically defined and enumerated amino acid residues.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it contains legal phraseology in the form of the word “said” (i.e., …with a virus expressing said protein) [emphasis added]. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The use of the term “Cremophor EL”, which is a trade name or a mark used in commerce, 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.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1-8 and 14-15 are objected to because of the following informalities: all of the identified claims are missing articles at the start of each claim. Claims 1-4 should say “An Adenovirus DNA-binding protein (DBP)…”, Claim 5 should say “A nucleotide sequence…”, Claim 6 should say “A plasmid…”, Claims 7-8 should say “An Adenovirus…”, Claim 14 should say “A cell…”, and Claim 15 should say “A pharmaceutical composition…”.
Appropriate correction is required.
Claim 8 is objected to because of the following informalities: it is suggested that it say “…selected from the group consisting of…”.
Appropriate correction is required.
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 7-8 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.
Regarding Claims 7-8, they both recite the limitation “Adenovirus or recombinant adenoviral vector”. The use of the word “or” implies that there should be a difference of some kind between the embodiments recited. Upon checking the definition Applicant provided in the Specification, however, it is now unclear how these two embodiments are actually different. In Paragraph 0032, Applicant states that “As used herein, the term ‘adenovirus’ refers to a virus or virus particles that can be categorized as an adenovirus, including all types and subtypes that occur naturally or have been recombinantly produced. In contrast, a ‘viral vector’ refers to a virus or viral particle that comprises a polynucleotide, which is exogenous to the viral genome, such as a transgene, and which is to be delivered to a host cell by in vivo, ex vivo or in vitro methods”. While Applicant attempts to distinguish between the two terms, the definition fails to provide clarity on how they differ as both encompass a virus or a virus particle and thus the same embodiment. It is suggested that the claim be amended by removing one of the recited options, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 7-8 are rejected on the grounds of being indefinite.
Claim 15 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.
Regarding Claim 15, it recites the limitation “Pharmaceutical composition comprising an adenoviral DNA-binding protein (DBP) of claim 1”. The use of the article “an” renders the claim indefinite as it is unclear if it is referencing the same adenoviral DNA-binding protein (DBP) which was introduced in Claim 1 or a different DBP. “A/An” is an indefinite article, while “the” is a definite article. “The” refers back to a specific molecule from Claim 1, while “A/An” can refer back to any non-specific molecule and is not clear that it is only referencing the molecule of Claim 1. It is suggested that the claim be amended by replacing “an” with “the”, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 15 is 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 Rejections - 35 USC § 112(a); First Paragraph
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 1-8 and 14-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the specific mutation, S354A, comprised in instant SEQ ID NO: 2, does not reasonably provide enablement for any and all possible mutations in the recited sequence motif of NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to an Adenoviral DNA-binding protein (DBP) comprising a mutation in the sequence motif NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH which inhibits adenoviral DNA replication in a cell infected with a virus expressing said protein.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Working examples. Only one working example of a DBP variant with a mutation in the NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH motif is disclosed in the specification, specifically S354A (see at least Paragraphs 0069-0070, 0080).
Guidance in the specification. The specification provides guidance towards DBP variants in HAdV type 5 in the two putative USP7-binding motifs (UBM), specifically 72-Pro-Ser-Thr-Ser-77 and 350-Ser-Gly-Lys-Ser-355, wherein the last Serine residue of each motif was mutated to an Alanine (see Paragraph 0012). The specification also provides guidance towards equivalent residues corresponding to the 350-Ser-Gly-Lys-Ser-355 motif present in HAdV type 5 in other HAdV types (see Paragraph 0014). Additionally, the specification provides guidance towards deletion of one the Serine residues in the 350-Ser-Gly-Lys-Ser-355 motif, deletion of any and all residues in said motif, insertion of residues within said motif, or substitution of any and all residues in said motif (see Paragraphs 0016-0024). Furthermore, the specification provides guidance towards DBP variants with mutations in five potential UBMs, 31-Pro-Ser-Pro-Ser-36; 72-Pro-Ser-Thr-Ser-77; 118-Val-Gly-Phe-Ser-123; 175-Pro-Iso-Val-Ser-180; and 350-Ser-Gly-Lys-Ser-355 (see Paragraphs 0069-0070).
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide variants of known sequences will function as such, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of the instant claims as broadly as they are currently claimed.
Claim 4 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an amino acid sequence which is 100% identical to instant SEQ ID NO: 2, does not reasonably provide enablement for variants of the claimed sequence with less than 100% sequence identity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to an Adenoviral DNA-binding protein (DBP) comprising a mutation in the sequence motif NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH which inhibits adenoviral DNA replication in a cell infected with a virus expressing said protein, wherein said protein comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 90% identity thereto.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Working examples. No working examples of the claimed variants are disclosed in the specification.
Guidance in the specification. The specification provides guidance towards constructs which are presumably 100% identical to the claimed sequence. The instant Specification, however, fails to disclose the critical or essential amino acid residues which must be present, aside from the claimed mutation, and any variants of the claimed sequence.
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide variants of known sequences will function as such, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of the instant claims as broadly as they are currently claimed.
Claims 5-8 and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an isolated nucleotide, an isolated plasmid, an isolated vector or an isolated cell comprising said nucleotide, does not reasonably provide enablement for a cell within a transgenic animal or a transgene therein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. Applicant broadly claims a host cell or a vector or nucleic acid/plasmid containing the Adenoviral DBP of claim 1 or a nucleic acid encoding said protein. The claims read on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the host cell, nucleic acid/plasmid, or vector.
State of the prior art/Predictability of the art. With respect to the unisolated host cells and transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et Al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second).
Working examples. No working example of a transgenic animal is disclosed in the specification. The only mentions of “transgene” in the instant Specification are in Paragraph 0008, which states in part that “attenuated adenoviruses could also be used as viral vectors in gene therapy processes for introducing a nucleic acid, such as a transgene into a subject” and Paragraph 0032, which states in part that “a ‘viral vector’ refers to a virus or viral particles that comprises a polynucleotide, which is exogenous to the viral genome, such as a transgene and which is to be delivered to a host cell by in vivo, ex vivo, or in vitro methods”.
Guidance in the specification. The specification provides guidance towards an Adenovirus or a recombinant adenoviral vector comprising a modified DBP or a nucleotide sequence encoding the same, a nucleotide sequence or plasmid encoding the same, and a cell that comprises a modified adenoviral DBP (see Paragraphs 0031-0036).
Amount of experimentation necessary. At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation “nucleotide sequence”, “plasmid”, “recombinant adenoviral vector”, and "cell" and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal. Applicant may consider using “purified” in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional polynucleotides that produce the claimed mutated DBP, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed mutated DBP is functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Claim 15 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a pharmaceutical or immunogenic composition comprising the adenoviral DBP of claim 1, does not reasonably provide enablement for a vaccine comprising the adenoviral DBP of claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to an Adenoviral DNA-binding protein (DBP) comprising a mutation in the sequence motif NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH which inhibits adenoviral DNA replication in a cell infected with a virus expressing said protein and a pharmaceutical composition or vaccine comprising an adenoviral DNA-binding protein (DBP) of claim 1. The instant Specification does not specifically define “vaccine”, but it states that the “vaccine is preferably effective against a disease that is caused by adenovirus infection selected from the group consisting of keratoconjunctivitis epidemica, acute respiratory diseases, pharyngoconjunctival fever, follicular conjunctivitis, gastroenteritis, pneumonia, and pharyngitis (see Paragraph 0042).
State of the prior art/Predictability of the art. Reasonable guidance with respect to preventing any viral infection relies on quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of viruses. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical infection and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Further, a preventive administration also must assume that the therapeutic will be safe and tolerable for anyone susceptible to the disease. Therefore, Applicant may provide data showing prevention in vivo.
As stated in Cross v. Iizuka, 753 F.2d 1040, 1050, 224 USPQ 739, 747 (Fed. Cir. 1985): [B]ased upon the relevant evidence as a whole, there is a reasonable correlation between the disclosed in vitro utility and an in vivo activity, and therefore a rigorous correlation is not necessary where the disclosure of pharmacological activity is reasonable based upon the probative evidence. (Citations omitted.) Therefore, in the absence of the in vivo data above, Applicant may also provide evidence of pharmacological activity that would reasonably correlate with prevention of infection.
In the case of virus vaccines, a reasonable nexus exists between neutralizing antibody generation and prevention of infection. Thus, a showing that an antigen within the recited immunogen scope can produce such antibodies would support enablement for use of said antigen in a vaccine and/or methods of preventing infection therewith of the virus comprising said antigen.
Burton (Nature Reviews Immunology, Vol. 2, Pg. 706-713, 2002) teaches neutralizing antibodies are crucial for vaccine-mediated protection against viral diseases (Abstract). Figure 1 divides antiviral activities of antibodies into two groups: activities against free virus and activities against infected cells. Actual block of infection (prevention of infection) is taught to be the role of neutralizing antibodies (Figure 1). Nonneutralizing antibodies thus cannot prevent infection, only treat an infection.
Adding to the unpredictability is the fact that not just any epitope of a target antigen/virus will lead to antibody generation, let alone that of neutralizing antibodies. Riddell (Journal of Virology, Vol. 74, No. 17, Pg. 8011-8017, 2000) at the abstract teaches patient sera reacts with some but not all B-cell epitopes on ORF7.1 protein. Thus, not just any epitope/antigen/immunogen will contribute to patient immunity against a virus. Sugiyama (Journal of Virology, Vol. 76, No. 4, Pg. 1691-1696, 2002) supports this by teaching in their abstract that even amongst known epitopes that lead to neutralizing antibodies in some species, another subject’s immune reaction will not necessarily generate antibodies against all said epitopes.
Burton (PNAS, Vol. 108, No. 27, Pg. 11181-11186, 2011) teaches three anti-HIV antibodies. Antibodies b12 and b6 bind CD4 binding sites while F240 binds gp41 (Abstract). All were tested for prevention of SHIV transmission to macaques (Abstract). While the two anti-gp120 antibodies have similar binding properties, b12 is strongly neutralizing and b6 is not (Abstract). F240 is nonneutralizing (Abstract). Compared to controls, the protection by b12 achieved statistical significance while no such protection was seen for either b6 or F240 (Abstract). Thus, the work of Burton supports the conclusion that neutralizing antibodies are required for prevention and so a functional vaccine should produce such. It also supports the idea that not just any peptide on protein may generate neutralizing antibodies that protect as evidenced by b12 and b6 performance above. Data are clearly required to calm the concerns of the prior art and make methods of viral infection prevention and vaccine products predictable.
Taken together, it is clear from the prior art that a PHOSITA cannot predict the preventative power of any immunogen. They must be shown data that supports such a conclusion. Without demonstration of neutralizing antibody production, for example, in the target population with the specific immunogen, no practitioner in this art would see any given immunogen as a functional, predictable prophylactic agent.
Working examples. No working examples of a pharmaceutical or immunogenic composition or a vaccine comprising the mutated adenoviral DBP are disclosed in the specification. All examples are hypothetical or prophetic in nature.
Guidance in the specification. The specification does provide guidance towards a pharmaceutical or immunogenic composition or a vaccine comprising the mutated adenoviral DBP. There is no in vitro or in vivo data provided, however, demonstrating protection or the generation of an immune response using a pharmaceutical or immunogenic composition or a vaccine comprising the mutated adenoviral DBP.
Amount of experimentation necessary. Additional research is required in order to determine how effective the claimed mutant Adenoviral DBP and nucleic acids encoding said protein would be at acting as part of a vaccine.
Claims 1-8 and 14-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the instant application, Applicant is attempting to claim the genus encompassed by an “Adenoviral DNA-binding protein (DBP) comprising a mutation in the sequence motif NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH which inhibits adenoviral DNA replication in a cell infected with a virus expressing said protein”. The instant specification provides guidance towards DBP variants in HAdV type 5 in the two putative USP7-binding motifs (UBM), specifically 72-Pro-Ser-Thr-Ser-77 and 350-Ser-Gly-Lys-Ser-355, wherein the last Serine residue of each motif was mutated to an Alanine (see Paragraph 0012). The specification also provides guidance towards equivalent residues corresponding to the 350-Ser-Gly-Lys-Ser-355 motif present in HAdV type 5 in other HAdV types (see Paragraph 0014). Additionally, the specification provides guidance towards deletion of one the Serine residues in the 350-Ser-Gly-Lys-Ser-355 motif, deletion of any and all residues in said motif, insertion of residues within said motif, or substitution of any and all residues in said motif (see Paragraphs 0016-0024). Furthermore, the specification provides guidance towards DBP variants with mutations in five potential UBMs, 31-Pro-Ser-Pro-Ser-36; 72-Pro-Ser-Thr-Ser-77; 118-Val-Gly-Phe-Ser-123; 175-Pro-Iso-Val-Ser-180; and 350-Ser-Gly-Lys-Ser-355 (see Paragraphs 0069-0070). Only one working example of a DBP variant with a mutation in the NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH motif, however, is actually disclosed and tested in the specification, specifically S354A (see at least Paragraphs 0069-0070, 0080). As such, Applicant has only disclosed one species of the genus being claimed and said species is not representative of the entire genus.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contributions to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle and Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient details that one skilled in the art can reasonably conclude that the invention had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the peptide variants can have any mutation in the recited sequence motif, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any peptide variants with the required limitation other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genus, the claims encompassing the same clearly fail the written description requirement.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014).
Overall, at the time the invention was made, the level of skill for preparing peptide variants and then selecting those peptides which meet the desired claim limitations was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identity peptide variants with the recited percent identity cutoff, the written description provision of 35 U.S.C. 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010). Absent the conserved structure provided by a core peptide sequence, the skilled artisan would not be able to visualize or otherwise predict, a priori, what any peptide which meets the limitations of the claims would look like structurally.
While applicant has described a few species within the genus recited, and the art may provide more, the genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide or nucleotide structures encompassed by the claimed/recited genera only defined by sequence identity. Any future peptide variants may or may not be encompassed, as if they are, they would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genus of peptide variants. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Therefore, the claims are rejected here.
Claim 4 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant application attempts to tie function to sequence identity in the context of an Adenoviral DNA-binding protein (DBP) comprising a mutation in the sequence motif NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH which inhibits adenoviral DNA replication in a cell infected with a virus expressing said protein, wherein said protein comprises the amino acid sequence of SEQ ID NO:2 or an amino acid sequence having at least 90% identity thereto. While a percent identity threshold is provided in the claim, the instant Specification fails to disclose the critical or essential amino acid residues which must be present, aside from the claimed mutation, and any variants of the claimed sequence. Applicant does not provide a definition for “variant” in the instant Specification and does not disclose what kinds of mutations would be tolerated, aside from the claimed mutation, in the claimed sequence. As such, it would be unclear to a person having ordinary skill in the art to know what to change and what not to change.
Furthermore, while it is not explicitly stated, it is assumed that the constructs used in the instant Specification have sequences which are 100% identical to the claimed sequence. Even if that is not the case, the data shown do not explicitly include any claimed variants having as little as 90% sequence identity, or even 91-99% sequence identity, raising questions about how effective these claimed variants would be in the data provided. Thus, it is not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genus being claimed by Applicant have not been identified or disclosed, aside from the claimed substitution mutation.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contributions to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle and Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient details that one skilled in the art can reasonably conclude that the invention had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the peptide variants can have any sequences which vary from instant SEQ ID NO 2 by as much as 10%, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any peptide variants with the required sequence identity other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genus, the claims encompassing the same clearly fail the written description requirement.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014).
Overall, at the time the invention was made, the level of skill for preparing peptide variants and then selecting those peptides which meet the desired percent identity cutoff was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identity peptide variants with the recited percent identity cutoff, the written description provision of 35 U.S.C. 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010). Absent the conserved structure provided by a core peptide sequence, the skilled artisan would not be able to visualize or otherwise predict, a priori, what any peptide or nucleotide which meets the recited percent identity cutoff would look like structurally.
While applicant has described a few species within the genus recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide or nucleotide structures encompassed by the claimed/recited genera only defined by sequence identity. Any future peptide variants may or may not be encompassed, as if they are, they would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genera of peptide variants. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Therefore, the claims are rejected here.
As such, it does not appear Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claim 4 does not meet the written description requirement.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 14 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Paragraph 0036 of the instant Specification specifically contemplates a human cell. It is suggested that the claim be amended so that it instead recites “An isolated cell”, but Applicant is free to amend the claim as they deem necessary.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5-8, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kondrajew (Kondrajew, Jana. 2017. Analyses on the role of Ubiquitin-specific Protease 7 during the course of productive infection with Adenovirus Type 5 – Dissertation. English translation.) (cited on IDS filed by Applicant on 10 November 2025).
Kondrajew teaches an Adenoviral DNA-binding protein (DBP) comprising a mutation in the sequence motif NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH, wherein said motif is Serine-Glycine-Lysine-Serine (SGKS), wherein said mutation is an amino acid substitution of the Serine residue located at the COOH terminus of the sequence motif to an Alanine, specifically wherein the mutation is S354A (see Page 7, Lines 28-30; Page 8, Lines 7-8; Page 74, Lines 5-13; Figure 16; Page 89, Lines 23-28), which reads on instant Claims 1-3. Kondrajew also teaches an Adenovirus type 5 comprising a nucleotide sequence encoding the mutated DBP, wherein said mutated DBP inhibits adenoviral DNA replication in a cell infected with a virus expressing said protein (see Page 33, Section 3.2 Table; Page 45, Lines 22-25 and Page 46, Lines 1-10; Page 102, Lines 9-31), which reads on instant Claims 1, 5, and 7-8. Additionally, Kondrajew teaches a plasmid comprising the nucleotide sequence encoding the mutated DBP (see Page 37, Section 3.3.3 Table), which reads on instant Claim 6. Furthermore, Kondrajew teaches a cell line comprising a plasmid comprising a nucleotide sequence encoding the mutated adenoviral DBP (see Page 30, Section 3.1.2 Table; Lines 7-11; Page 44, Lines 7-15), which reads on instant Claim 14.
For at least these reasons, Kondrajew teaches the limitations of instant Claims 1-3, 5-8, and 14 and anticipates the invention encompassed by said claims.
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.
Claims 1-8 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Kondrajew (Kondrajew, Jana. 2017. Analyses on the role of Ubiquitin-specific Protease 7 during the course of productive infection with Adenovirus Type 5 – Dissertation. English translation.) (cited on IDS filed by Applicant on 10 November 2025), Gall et al. (WO 2009/076542 A1, Published 18 June 2009) (cited on IDS filed by Applicant on 10 November 2025), and Agrawal et al. (US 2018/0000926 A1, Published 04 January 2018).
Kondrajew teaches an Adenoviral DNA-binding protein (DBP) comprising a mutation in the sequence motif NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH, wherein said motif is Serine-Glycine-Lysine-Serine (SGKS), wherein said mutation is an amino acid substitution of the Serine residue located at the COOH terminus of the sequence motif to an Alanine, specifically wherein the mutation is S354A (see Page 7, Lines 28-30; Page 8, Lines 7-8; Page 74, Lines 5-13; Figure 16; Page 89, Lines 23-28). Kondrajew also teaches an Adenovirus type 5 comprising a nucleotide sequence encoding the mutated DBP, wherein said mutated DBP inhibits adenoviral DNA replication in a cell infected with a virus expressing said protein (see Page 33, Section 3.2 Table; Page 45, Lines 22-25 and Page 46, Lines 1-10; Page 102, Lines 9-31). Additionally, Kondrajew teaches a plasmid comprising the nucleotide sequence encoding the mutated DBP (see Page 37, Section 3.3.3 Table). Furthermore, Kondrajew teaches a cell line comprising a plasmid comprising a nucleotide sequence encoding the mutated adenoviral DBP (see Page 30, Section 3.1.2 Table; Lines 7-11; Page 44, Lines 7-15).
Kondrajew does not teach an Adenoviral DBP wherein said protein comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 90% identity thereto or a pharmaceutical or immunogenic composition comprising said mutated adenoviral DBP.
Gall et al. teach a live attenuated serotype 14 Adenovirus (see Abstract) as well as a composition comprising said Adenovirus (see Paragraph 0009), specifically a pharmaceutically composition (see Paragraph 0055). Gall et al. also teach wherein said live attenuated Adenovirus has a mutated DBP, which affects viral DNA replication and thus the ability of the virus to propagate (see Paragraph 0018).
Agrawal et al. teach the use of an attenuated or replication-incompetent Adenovirus for generating an immune response against a viral antigen, wherein the Adenovirus is modified via mutations in regions such as the E2A gene, which encodes for the DBP (see Paragraphs 0009, 0042, 0058, 0066, 0296). Agrawal et al. also teach SEQ ID NO: 161, which corresponds to the wild-type sequence for the HAdV type 5 DBP and is 100% identical to instant SEQ ID NO: 1 (see Sequence Listing).
A person having ordinary skill in the art would have been motivated to modify the teachings of Kondrajew with those of Gall et al. and Agrawal et al. in order to develop a pharmaceutical composition comprising an Adenovirus with an impaired ability to replicate. Kondrajew teaches an Adenovirus with a mutated DBP with a reduced capacity to replicate in infected cells. In other words, Kondrajew teaches an attenuated Adenovirus, similar to the attenuated Adenovirus of Gall et al. Both references teach an Adenovirus comprising a mutated DBP, which affects the ability of the virus to replicate its DNA and thus generate viral progeny. While Gall et al. teach a different serotype from Kondrajew, it would have been obvious to apply the teachings of Gall et al. to the attenuated Adenovirus of Kondrajew and formulate the attenuated Adenovirus in the pharmaceutically acceptable composition of Gall et al. Agrawal et al. also teach the use of a replication-deficient or attenuated Adenovirus for the purposes of generating an immune response in a subject against a particular virus. While Agrawal et al. is focused on treating Hepatitis C virus (HCV), it would have been obvious to apply the teachings of Agrawal et al. to those of Kondrajew and Gall et al. Additionally, a skilled artisan would have been motivated to modify the wild-type DBP of Agrawal et al. with the S354A mutation of Kondrajew since Kondrajew teaches that an Adenovirus comprising a DBP with said mutation has an attenuated phenotype. The composition of Gall et al. would have provided a safe and effective way to administer the attenuated Adenovirus of Kondrajew and Agrawal et al. to a subject for the purpose of generating an immune response against virus, in this case an Adenovirus. The attenuated Adenovirus of Kondrajew and Agrawal et al. would be replication-deficient and thus would be safer to administer to a subject as it would result in fewer side effects upon administration. As such, the combination of these teachings renders the invention encompassed by the instant claims obvious.
For at least these reasons, instant Claims 1-8 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Komatsu et al. (Komatsu T, Nagata K, Wodrich H. An Adenovirus DNA Replication Factor, but Not Incoming Genome Complexes, Targets PML Nuclear Bodies. J Virol. 2015 Nov 25;90(3):1657-67.)
Komatsu et al. teach that Adenoviral DBP independently targets promyelocytic leukemia protein nuclear bodies (PML-NBs) and that DBP oligomerization is required to selectively recruit the PML-NB components Sp100 and USP7. This reference has not been utilized, as rejection would have been redundant to those set forth above.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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