DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1-2, 6-15, 18, 21-23, and 26-29) and the following species elections:
SEQ ID NO: 16 for the polynucleotide, derived from SARS-coV-2 spike protein and based on claim 2(r)
Adenoviral vector for the viral vector
Adenovirus for the virus
in the reply filed on 19 May 2026 is acknowledged.
Claims 13 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and species, there being no allowable generic or linking claim.
Claim Status
3. Claims 3-5, 16-17, 19, 24-25, and 30-32 are canceled.
Claims 13 and 20 are withdrawn.
Claims 1-2, 6-12, 14-15, 18, 21-23, and 26-29 are under consideration.
Priority
4. The Instant Application is a National Stage (371) of PCT/GB2022/050759, filed 25 March 2022, which claims priority to GB2104320.3, filed 26 March 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 19 May 2026 and 21 November 2023 were filed before the mailing date of the Non-Final Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
6. 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.
Nucleotide and/or Amino Acid Sequence Disclosures
7. 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:
8. 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
9. 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.
10. The disclosure is objected to because of the following informalities: on page 32, line 14, 108 appears to be a typo and should read 108 instead.
Appropriate correction is required.
Claim Objections
11. Claims 2 and 28 are objected to because of the following informalities:
Regarding claim 2, a comma should be inserted before “or” for every instance of a list for clarity.
Regarding claim 28, “the” should be inserted before “viral particles”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
12. 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.
13. Claims 1-2, 6-12, 14-15, 18, 21-23, and 26-29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the plasma membrane". There is insufficient antecedent basis for this limitation in the claim.
Claims 2, 6-12, 14-15, 18, 21-23, and 26-29, which are dependent on claim 1, are similarly rejected.
Claim 2 recites the limitation "the cytoplasmic tail". There is insufficient antecedent basis for this limitation in the claim.
Claim 6, which depends on claim 2, is similarly rejected.
Claim 2 is rejected for claiming the limitation of “the cytoplasmic tail from infectious bronchitis virus in which the dilysine motif is substituted with alanine, the tyrosine internalization sequence is also mutated to replace the tyrosines with alanine” without providing an appropriate frame of reference for said sequence. Said frame of reference can be provided by referencing a sequence disclosed within the application (i.e. a sequence with a SEQ ID NO: identifier) or by referencing a start position for said sequence (i.e. “…wherein said nucleotide is at position X from the starting ATG of the open reading frame…” or “…wherein said amino acid is at position X from the starting methionine of the protein…”).
Claim 6, which depends on claim 2, is similarly rejected.
Claim 9 recites the limitation "the motif". There is insufficient antecedent basis for this limitation in the claim.
Claim 12 is rejected for claiming the limitation of “at the -3 and -4 positions” without providing an appropriate frame of reference for said sequence. Said frame of reference can be provided by referencing a sequence disclosed within the application (i.e. a sequence with a SEQ ID NO: identifier) or by referencing a start position for said sequence (i.e. “…wherein said nucleotide is at position X from the starting ATG of the open reading frame…” or “…wherein said amino acid is at position X from the starting methionine of the protein…”). Examiner is interpreting this to read on the 3rd and 4th amino acid from the end of SEQ ID NO: 7, as exemplified on page 10 of the Instant Specification.
Regarding claim 18, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 29, the term “expanding” is unclear as it could be interpreted as expanding the cells and virus or expansion of just the viruses. See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
Claim Rejections - 35 USC § 112(a) – Written Description
14. 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.
15. Claims 1-2, 6-12, 14-15, 18, 20-23, and 26-29 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.
The claims above are drawn to a polynucleotide encoding an antigen from a virus wherein the antigen has been modified to reduce membrane fusion and/or the formation of syncytia. Thus, it is clear that the breadth of the recited peptides in the claims far overreaches Applicant’s contribution as disclosed in the specification and so this rejection is made. One of ordinary skill in this art cannot conclude that Applicant was in possession of just any polynucleotide capable of reducing membrane function and/or formation of syncytia. An enormous breadth of polynucleotides is thus not represented by Applicant at all. Even if the prior art is aware of some polynucleotides, the totality of known polynucleotides with this function would not be representative of the entire genus for the reasons discussed below.
“[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 contribution 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 & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor 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 the 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 inhibitors can have any sequence, 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 other peptides with the required function 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.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members.
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since there are no polynucleotides encoding an antigen from a virus with the ability to reduce membrane fusion and/or the formation of syncytia taught by Applicant, and mutated polypeptides would vary in structure, there is no correlation between structure and function between the members of the recited or any peptide genus. Additional mutated polypeptides could read on any and all combinations of amino acids. Thus, since there is no correlation between structure and peptide function across the entire genus, functional language should not be used to define a peptide genus. Rather, structure should be used, including the core peptide sequence required for said function.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since the genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
Overall, at the time the invention was made, the level of skill for preparing peptides and then selecting those peptides with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides with the recited functional properties, 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 inhibitory peptide sequence, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what any peptide with a particular set of functional properties would look like structurally.
Since no mutations are taught in the specification of the recited genus above, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe such a massive genus. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe said genus.
Owed to the variation among the peptides of the genus as broadly as currently claimed, it is very difficult to provide adequate representation of the functionally defined peptide genus. There is unlikely to be any structure (subsequence) shared by the entire genus. If there is a subsequence common to all or some of Applicant’s species, then the claims should recite that as part of the peptide genus to provide adequate representation of the actual disclosed/possessed group. Also, the disclosure of one group of highly related peptides does not guide one of skill to the next peptide of the genus with said function. Finding a another said peptide would require mutation and it is well-known in this art that mutation of peptides leads to specific function loss.
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, J. Cell Bio., 1990, 111: 2129-2138). 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, Molecular and Cellular Biology, 1988, 8: 1247-1252). 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 (PNAS, 1991, 88: 2658-2662) 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, 2000, 13: 475-484) 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 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 mutagenesis. Importantly, binding can still occur after mutation, 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 (J. Biol. Chem., 1997, 272: 21201-21206) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Thus, 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 structures encompassed by the claimed/recited genus only defined by function. Any future peptide may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genus of peptides. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, 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. Therefore, it is recommended that the instant claims be amended to recite that the peptide genus must comprise the core peptide responsible for the recited function as this would define the structure/function relationship of the species Applicant possesses.
Claim Rejections - 35 USC § 112(a) – Enablement
16. In making a determination as to whether an application has met the requirements forenablement under 35 U.S.C. 112 ¶ 1, the courts have put forth a series of factors. See, In reWands, 8 USPQ2d 1400, at 1404 (CAFC 1988). The factors considered include: (1) the breadth of the claims, (2) the nature of the invention, (3) the relative skill of those in the art, (4) the presence or absence of working examples, (5) the amount of direction or guidance provided, (6) the state of the prior art, (7) the level of predictability in the art, and (8) the quantity of experimentation necessary.
17. Claims 1-2, 6-12, 14-15, 18, 20-23, and 26-29 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 isolated polynucleotides, vectors, and cells, does not reasonably provide enablement for unisolated polynucleotides, vectors, and cells. 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 claims recite a polynucleotide, viral vector, or host cells, which include includes transgenes and transgenic animals respectively since none are isolated.
The nature of the invention are products and methods for making a polynucleotide encoding a modified viral antigen.
The level of skill of one of ordinary skill in this art is high.
The specification does not give a definition for “isolated”, nor does it indicate that the polynucleotides, vectors, or host cells are isolated. Therefore, these words will be given their broadest reasonable interpretation to one of ordinary skill in the art as discussed above. With respect to transgenes within animals and transgenic animals themselves, none were made here.
With respect to the unisolated host cells and vectors as transgenes, 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, Theriogenology, 1996, 45: 57-68).
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, J. Biotechnol., 1994, 34: 269- 287). 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, Current Opinions in Biotechnology, 1992, 3: 548-553). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, 2009, 32: 107-121) 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). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the antibody and antibody fragments of the instant claims.
The Examiner notes here, in addition to these issues, even assuming arguendo a person of ordinary skill could make a host organism with functional transgene that encodes the instantly recited antibody, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
The art is well-aware of side effects caused by therapeutic antibodies such as the one instantly recited. In a transgenic cell or animal that expresses the same, the antibody will exert any possible side effect it can. It is not administered but chronically present and so such side effects are chronic and potentially more serious than any from an administered antibody. Hansel (Nat. Rev. Drug. Discov., 2010, 9: 325-337) teaches in their table 1 on page 328 numerous exemplary side effects from licensed monoclonal antibodies to include: increased bleeding risk, infection, heart failure, cancer, thyroid disorder, autoimmune reactions, and cytokine release syndrome (CRS) to name only a few. One or more such effects, or similar, may occur with the therapeutic antibody instantly recited when administered and indeed be exacerbated by chronic exposure due to internal expression. The instantly encoded antibody may very well target related or unrelated proteins in the transgenic host, leading to such side effects. For all these reasons, transgenes in transgenic animals and the animals themselves are not enabled.
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 "host cell" and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal using, for example, “isolated”. 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 transgenes and transgenic animals encompassed by the instant claims.
18. Claims 2 and 7-9 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 a defined and tested set of modifications/mutations, does not reasonably provide enablement for any and all possible mutations of the polypeptide. 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 the invention commensurate in scope with these claims.
The claims are drawn a polypeptide encoding a modified viral antigen, compositions thereof, and methods of making thereof.
The nature of the invention are products and methods for making a polynucleotide encoding a modified viral antigen.
The level of skill of one of ordinary skill in this art is high.
The specification provides examples for the cytoplasmic tail after mutation (SEQ ID NOs: 7-8), and substitution of tryptophan residues into SEQ ID NO: 1 (see pages 12-13), but does not contemplate any other mutations/modifications.
The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, conservative 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. Cell Bio., 1990, 111: 2129-2138). 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., Mol. Cell. Biol., 1988, 8: 1247-1252). 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 (PNAS, 1991, 88: 2658-2662) 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, 2000, 13: 475-484) 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 (J. Biol. Chem., 1997, 272(43): 27155-27159) 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 (Nat. Genet., 1998, 18: 150-154) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Hum. Mol. Genet., 2009, 18(18): 3353-3364) 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 (J. Biol. Chem., 1997, 272: 21201-21206) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
With respect to the use of peptides in the treatment of a disease such as cancer, the state of the art at the time of filing was such that it was unpredictable whether or not a peptide would function therapeutically. Their functionality depends, in part, on whether or not they reach their intended target in a sufficient quantity as to cause a therapeutic effect. Mendoza (Arch. Immunol. Ther. Exp., 2005, 53: 47-60) teaches that peptides derived from larger molecules that are important modulators of apoptosis are frequently becoming leads for the development of anticancer therapeutics (Pg. 48, Column 2, Paragraph, first partial). However, they also state that natural peptides have low bioavailability and short half-life in the mammalian circulation system, while synthetic peptides have potential cytotoxicities (Pg. 57, Column 1, Paragraph, last full). Due to these characteristics, systematic testing in in vivo as well as in vitro settings must be done rigorously to verify peptide applications in the clinic (Pg. 57, Column 1, Paragraph, last full). Taken together, barring experimental evidence, no peptide can merely be assumed to function in the treatment of a disease, for example cancer, in vivo just because it functions as an inhibitor in vitro.
Since the art teaches that it is unpredictable whether or not peptide variants of known inhibitors will function as such and it is also unpredictable that even a known inhibitory peptide that functions in vitro will function in vivo, it would also be unpredictable to that the polypeptide variants will retain their original function or function as desired. Since the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed.
Claim Rejections - 35 USC § 102
19. 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.
20. Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lontok (01 June 2004, J. Virol., 78(11)) (See IDS filed 21 November 2023).
Regarding claims 1-2, Lontok teaches a VSV-G with its cytoplasmic tail replaced with the IBV S cytoplasmic tail (Results, ¶ 2) with the following mutations: “Replacing the two lysine residues with alanines (G-S2A) resulted in expression on the cell surface with a patchy distribution. Internal staining of cells expressing G-S2A demonstrated that this protein was largely localized in the Golgi region and numerous small puncta throughout the cytoplasm. Upon closer examination of the IBV S-tail sequence, we observed a potential tyrosine internalization signal (YYTF) (Fig. 1A) (reviewed in reference 3) upstream of the dilysine signal. Replacing the two tyrosine residues in this sequence with alanines (G-S4A) resulted in homogeneous plasma membrane distribution, without the puncta seen with G-S2A (Fig. 2B).” (Results, ¶ 3). In addition, Lontok teaches “The cloned Vero-adapted IBV S gene contained 14 amino acid changes compared to the published Beaudette IBV S sequence” (Plasmids and expression vectors, ¶ 1). Therefore, the resulting IBV cytoplasmic tail sequence has the dilysine motif substituted with alanine, the tyrosine internalization sequence mutated into alanines, and other amino acid mutations.
See Figures 1 (left) and 2 (right):
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Wherein “Wild-type S was not detected at the plasma membrane, and it accumulated in intracellular compartments resembling the ER and ERGIC (see below). The mutant lacking the dilysine signal (S2A) was readily detected at the cell surface as well as throughout the secretory pathway.” (Results, ¶ 1). Therefore substitutions for the 4 alanines resulted in more antigen at the plasma membrane, as claimed. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). “Products of identical chemical composition can not have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Lontok also teaches the possession of a polynucleotide encoding the antigen: “We cloned the cDNA encoding IBV S by reverse transcription-PCR) using RNA from Vero cells infected with the Vero-adapted strain of IBV.” (Plasmids and expression vectors, ¶ 1).
Claim Rejections - 35 USC § 103
21. 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.
22. 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.
23. Claims 1-2, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Lontok (01 June 2004, J. Virol., 78(11)) (See IDS filed 21 November 2023) in view of GenBank AAF64462.1 (26 June 2016, NCBI BLAST, spike protein precursor, partial [Infectious bronchitis virus]).
Regarding claims 1-2, Lontok teaches a VSV-G with its cytoplasmic tail replaced with the IBV S cytoplasmic tail (Results, ¶ 2) with the following mutations: “Replacing the two lysine residues with alanines (G-S2A) resulted in expression on the cell surface with a patchy distribution. Internal staining of cells expressing G-S2A demonstrated that this protein was largely localized in the Golgi region and numerous small puncta throughout the cytoplasm. Upon closer examination of the IBV S-tail sequence, we observed a potential tyrosine internalization signal (YYTF) (Fig. 1A) (reviewed in reference 3) upstream of the dilysine signal. Replacing the two tyrosine residues in this sequence with alanines (G-S4A) resulted in homogeneous plasma membrane distribution, without the puncta seen with G-S2A (Fig. 2B).” (Results, ¶ 3). In addition, Lontok teaches “The cloned Vero-adapted IBV S gene contained 14 amino acid changes compared to the published Beaudette IBV S sequence” (Plasmids and expression vectors, ¶ 1). Therefore, the resulting IBV cytoplasmic tail sequence below has the dilysine motif substituted with alanine, the tyrosine internalization sequence mutated into alanines, and other amino acid mutations. See Figures 1 (left) and 2 (right):
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Wherein “Wild-type S was not detected at the plasma membrane, and it accumulated in intracellular compartments resembling the ER and ERGIC (see below). The mutant lacking the dilysine signal (S2A) was readily detected at the cell surface as well as throughout the secretory pathway.” (Results, ¶ 1). Therefore substitutions for the 4 alanines resulted in more antigen at the plasma membrane, as claimed. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). “Products of identical chemical composition can not have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Lontok also teaches the possession of a polynucleotide encoding the antigen: “We cloned the cDNA encoding IBV S by reverse transcription-PCR) using RNA from Vero cells infected with the Vero-adapted strain of IBV.” (Plasmids and expression vectors, ¶ 1).
Regarding claim 6, the IBV cytoplasmic tail sequence of Lontok does not exactly match SEQ ID NO: 7. However, GenBank AAF64462.1 (‘Sbjct’) teaches a partial IBV spike protein that has a C-terminal end that matches SEQ ID NO: 7 (‘Query’) with the four alanine mutations undone:
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It would have been obvious to one of ordinary skill to take the IBV cytoplasmic tail of the IBV strain from GenBank AAF64462.1 and further mutate the dilysine and tyrosine internalization sequences to alanine, as discussed by Lontok. A rationale to support a conclusion that a claim would have been obvious is that there is some teaching, suggestion, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, G. and 2143.02).
24. Claims 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Lontok (Supra) in view of GenBank AAF64462.1 (Supra) as applied to claims 1-2, and 6 above, and further in view of Liao (10 February 2015, ACS, 54(9)) (See IDS filed 21 November 2023).
Regarding claims 7-12, Lontok and GenBank AAF64462.1 make claim 1 obvious, as discussed supra. All discussion thereon incorporated here. GenBank AAF64462.1 teaches the sequence below (‘Sbjct’) (further expanded from the sequence discussed supra), which reads on SEQ ID NO: 16 (‘Query’) with the four alanine mutations undone and the unmutated WXWXXW motif:
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None of the references teach mutating the WXWXXW motif into AXAXXA. However, Liao teaches a highly-conserved tryptophan (Trp)-rich membrane proximal external region (Abstract) that can be found across all members of Coronaviridae, including IBV (Tables 1-2):
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Liao teaches “Our study using Trp → Ala and Trp → Phe MPER analogues showed that Trp residues were essential for lipid mixing. This Trp-dependent effect was pronounced in the Trp → Ala analogues when the side-chain indole moiety of Trp was replaced by an alkyl moiety of Ala. In biological membranes, M-wt was found to be retained on Vero E6 cell membranes. In contrast, M-3W3A did not exhibit any binding to cell membranes.” (Discussion, ¶ 2). Therefore, it would have been obvious to one of ordinary skill before the filing date to take the MPER region of IBV and do the triple alanine substitution in order to prevent binding to cell membranes. This could be useful for virus attenuation and safety of vaccines by limiting the natural infectivity of the antigen. Additionally, the mutations yield a functional protein and at the very least, using this protein would result in predictable results. Furthermore, the IBV sequence in table 2 starts at the residue LKTY which aligns with the fragment taken from the full length of GenBank AAF64462.1, so it would be further obvious to take the IBV fragment from those residues to the end of the C-terminus. This fragment in combination with the dilysine and tyrosine internalization sequence makes SEQ ID NO: 16 obvious. The resulting sequence would predictably have the AA residues at the -3 and -4 positions, which would read on the dilysine signal to alanine substitution. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
25. Claims 14-15, 18, 21-23, and 26-29 are rejected under 35 U.S.C. 103 as being unpatentable over Lontok (Supra), GenBank AAF64462.1 (Supra), and Liao (Supra) as applied to claims 7-12 above, and further in view of van Santen (US 20190046634 A1; Published 14 February 2019) and Grieger (February 2016, Molecular Therapy, 24(2): 287-297).
Regarding claims 14-15 and 18, 21-23, and 28-29, Lontok and GenBank AAF64462.1 make claim 1 obvious, as discussed supra. All discussions thereon incorporated here. Van Santen teaches methods and products in relation to an IBV S protein ectodomain (Abstract). Van Santen further teaches “The recombinant viral nucleic acid may function as a vector for the immunogenic IBV S protein by virtue of the recombinant viral nucleic acid containing foreign DNA or RNA.” (¶ [0080]). Suitable viral vectors include adenoviruses (¶ [0081]). Since the encoded protein will be immunogenic, it is immediately obvious to a PHOSITA that the adenovirus particles carrying the same are obvious and obviously a vaccine component. Thus, claim 26 is obvious here. Therefore, it would have been obvious to one of ordinary skill to take the methods of Van Santen and apply them to the polynucleotide and antigens made obvious by Lontok and GenBank AAF64462.1. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Van Santen does not teach viral particles or a CMV promoter. However, Grieger teaches “Using the triple transfection method, the suspension HEK293 cell line generates greater than 1 × 105 vector genome containing particles (vg)/cell or greater than 1 × 1014 vg/l of cell culture when harvested 48 hours post-transfection.“ (Abstract) using rAAV vectors (Introduction, ¶ 2) and CMV promoter (Page 290, ¶ 1). Therefore, it would have been obvious to one of ordinary skill to take the viral vector made obvious by Van Santen and further use the methods of Grieger to make adenoviral vectors and viral particles that will contain the polynucleotide encoding the antigen, said antigen being encoded also by a functional promoter well known like the CMV promoter. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02). Thus, claims 28-29 are obvious here.
Regarding claims 26-27, Van Santen teaches “The recombinant viral nucleic acid, packaged in a virus may be introduced into a vaccinee by standard methods for vaccination with live vaccines.”
(¶ [0080]) and that the compositions may be administered orally (¶ [0062]).
Conclusion
26. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA E LY whose telephone number is (571)272-5169. The examiner can normally be reached Monday - Thursday, 8:00 am - 5:00 pm EST.
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/KRISTINA E. LY/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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