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 .
Claim Status
Claims 1 and 3-32 are pending. Claims 1, 10, and 14 were amended; and claims 22-32 were newly added in the Reply filed 3/05/2026. Claims 3-8, 11-13, 15-21, and 24-26 are withdrawn. Claims 1, 9-10, 14, 22-23, and 27-32 are presently considered.
Election/Restrictions
Applicant’s election without traverse of Group I (polypeptides, original claims 1-2, 9-11, 13-141) in the reply filed on 6/5/2024 was previously acknowledged. The traversal-in-part of the originally elected species of SEQ ID NO: 4 wherein amino acid 284 is N, amino acid 287 is D, amino acid 291 is D, amino acid 307 is L, amino acid 311 is D, amino acid 313 is N, amino acid 315 is D, and amino acid 322 is N, was previously acknowledged (see Action mailed 9/12/2024 at 2-5), but not found persuasive for reasons of record (see id).
The originally elected species was rejected as anticipated in the Action mailed 9/12/2024 (see Action mailed 9/12/2024 at 12-14 and 14-17).
In the Reply filed 3/12/2025, instant claim 1 was amended to exclude the originally elected species by requiring that the claimed peptide comprise “at least one substitution” at positions N284, D287, D291, L307, D311, N313, D315 relative to instant SEQ ID NO: 2.
The amended claim scope filed 3/12/2025 was then rejected as obvious in view of conservative substitutions of Santos et al.2 as evidenced by NCBI GenBank: ADP02444.13 (see, e.g., Action mailed 5/12/2025 at 11-16).
In the Reply filed 11/12/2025, instant claim 1 was amended to a polypeptide having >95% but <100% sequence identity with either SEQ ID NO: 2 or 4, but was amended to specifically require a substitution at D291 of SEQ ID NO: 2. This claim scope was rejected for reasons of record (see, e.g., Action mailed 12/05/2025 at pages 8-24).
In the Reply filed 03/05/2026, instant claim 1 was amended to require a polypeptide having an amino acid sequence as set forth in SEQ ID NO: 2 or SEQ ID NO: 4, wherein the polypeptide comprises a substitution at the amino acid position of D291 of SEQ ID NO: 2.
Accordingly, the amended claim scope of amended claim 1, as filed 3/05/2026, is understood to continue reading upon the previously examined sequence of
MADLLPTVKVSDLPTATESFEGDYLVVDQSDATRKSTWSDMFSRFGLMRLFSFQEGGTLVSPKDQVIDRSTNRIYQWTGAYPKLVPADSTPETTGGVGEGAWSANDPSLRGDLAGANGSTFIGGPAGTVAQSLDGFVTPAQFMGKYPTTTEAVTALAAYAKENKKAVLAWGWNLVLETSVYIDGVEWYGGSFNQTGGNRYMYLSNSTFRWVTFTGVCTRHYGGRLIITDSSWVNNTNTAAMLLQALPIEGTIDILDSDFRGCKYGILQQGTGALVTRARFARLNFNDLTGDAIECNVVQRHYKAGGLTIEDINIDNINNTDNSPNWGIGIGVAGQGPYGANASDDQYVSGIIIRNVKMRRVRQCIHFELCRDFKVENVEVYPDASVSNGTLLASGGVVCYGCKDYIIDGVRGEMVNGATRFIYFGWGVNQGTFAAPCRDFTLRNVRTHTGLVDIPVSAMDDWTNDVKVEDIECHTFKYRGLVSKLRLADIRCKQFDGIGDYEAGQGEAGGAMKRWAWCSAEIININSLDDNGVANGKFGQVGFDHLTTYGCNFDVVQHSKTNGNRGVILLNAGNIYISDNDDFPQGKEFVKGDIILKKTGGMFVVETGGSYIEPNDFIKATVVGSKTIECAADSSIRQPWATRAFKSAGLQLTIPGAGPGGADLQTTVIRAPYQKGAWITPFYLDIADPIQTATPDNTALVSTNPVVYSERT
wherein, the polypeptide comprise a substitution at position D291 (bolded, highlighted, and underlined above) (see, e.g., instant claim 1).
Per MPEP § 803.02, examination has now been extended to non-elected polypeptides, namely a conservative variant of NCBI GenBank: ADP02444.1 sharing >99.8% identity with instant SEQ ID NO:2, and differing from instant SEQ ID NO: 2 only by a single conservative substitution at D291, namely a D291E substitution. The non-elected species has been deemed obvious in view of the prior art as applied below.
Claims 3-8, 11-13, and 15-21 remain withdrawn for reasons of record. Regarding newly added claims, claims 24-25 are withdrawn as directed to a non-elected species, and claim 26 is withdrawn as directed to a non-elected invention. It is prima facie unknown if SEQ ID NO: 2 having a D291E substitution reads upon amended or newly added claims 10, 14, 22-24 and 27-32 because the “wherein” clauses fail to correspond to any structure/function relationship of record reasonably informing artisans if such species is included or excluded by such potential functional limitations. If these claims exclude the presently examined species, they are properly withdrawn. However, for purposes of examination in view of the prior art in the instant action, the “wherein” clauses at claims 10, 14, 22-24, and 27-32 are presumably satisfied by all embodiments satisfying the structurally complete limitations set forth in the body of instant claim 1 (see explanation provided in the claim interpretation section, below).
Claims 3-8, 11-13, 15-21, and 24-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or non-elected species, there being no allowable generic or linking claim. Applicant timely traversed the requirement in the reply filed on 6/05/2024.
Accordingly, claims 1, 9-10, 14, 22-23, and 27-32 are presently considered.
Priority
The priority claim to US Provisional 63/018,951 (May 1, 2020) is acknowledged.
Information Disclosure Statement
No IDS was filed in the Reply submitted 3/05/2026.
Applicant is advised that one or more claims have been rejected as directed to new matter under 35 USC 112(a). Therefore, Applicant is advised that any post-filed posters, dissertations, publications, presentations, etc. pertaining to SEQ ID NO: 2 or related sequences, published before the effective filing date of the instant Application (i.e., 05/08/2023), is pertinent to the patentability of the instant invention.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Amended claim 1 is representative of the pending claim scope and presently recites:
1. A polypeptide having an amino acid sequence as set forth in SEQ ID NO: 2 or SEQ ID NO: 4, wherein the polypeptide comprises a substitution at the amino acid position of D291 of SEQ ID NO:2.
The applicable claim interpretation is set forth below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
Claim 1 recites the phrase “A polypeptide having an amino acid sequence as set forth in SEQ ID NO: 2 or SEQ ID NO: 4”. The Office interprets claims directed to sequence identifiers as follows: The phrase “A biopolymer comprising a sequence of SEQ ID NO: 1” encompasses biopolymers comprising the full-length SEQ ID NO: 1 and also any subsequence of 2 or more units within SEQ ID NO: 1. The phrase “A biopolymer comprising the sequence of SEQ ID NO: 1” encompasses only biopolymers comprising the full-length of SEQ ID NO: 1. If the language is changed to closed, replacing “comprising with “consisting of, the first example above would encompass any biopolymer sequence of two or more units fully contained within SEQ ID NO: 1, whereas the second example would be limited to the exact biopolymer as specified by SEQ ID NO: 1, and nothing more or less. If qualifying language is present (i.e., “polynucleotide”, “protein”, “polypeptide”, “oligopeptide”, etc.) the specification is consulted to determine whether or not an explicit definition is provided that imposes a lower limit on the size of biopolymer encompassed by the qualifying terminology. Applicant is advised that claim 1 currently reads upon sequences comprising dipeptides, tripeptides, and other fragments; this is consistent with the description in the original disclosure (see, e.g., Spec. filed 5/08/2023 at 14 at line 28 to page 15 at line 5). Examination has not yet proceeded to any embodiments lacking >99% sequence identity relative to the full-length of instant SEQ ID NO:2. If this is not intended, Applicant should amend the claim to utilize definite articles rather than indefinite articles.
The recitation at amended claim 1 of “substitution at the amino acid position of D291 of SEQ ID NO: 2” is not limited to naturally-occurring L-amino acids in view of the specification (see, e.g., Spec. filed 5/08/2023 at 33 at line 10 to 36 at line 31), but instead explicitly includes D-amino acids.
At claims 10, 14, 22-23, and 27-32, the claims recite “wherein” clauses that fail to meaningfully correspond to any structure/function relationship of record. For purposes of applying prior art under 35 USC §102 and §103, the “wherein” clauses are reasonably inferred to correspond to recitations of intended and expected results fully satisfied by all polypeptides that satisfy the structural limitations of amended claim 1 (i.e., any polypeptide “having an amino acid sequence as set forth in SEQ ID NO: 2 or SEQ ID NO: 4, wherein the polypeptide comprises a substitution at the amino acid position of D291 of SEQ ID NO: 2”). This interpretation is reasonable because the “wherein” clauses do not appear to correspond to any meaningful functional limitations of record since no structure/function relationship commensurate in scope with such limitations and claim scope exists on record; furthermore, per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not limit a claim to a particular structure”). However, the alternative interpretation of such clauses (i.e., that they are functional limitations) has been addressed under 35 USC §112, below.
Additional claim interpretations are set forth below.
Withdrawn Claim Rejections
The rejection of claims 10 and 14 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is withdrawn in view of the amendments filed 3/05/2026. However, the amendments filed 3/05/2026 have raised additional issues, necessitating the new and/or revised rejections set forth below.
The rejection of claims 10 and 14 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, is withdrawn in view of the amendments filed 3/05/2026. However, the amendments filed 3/05/2026 have raised additional issues, necessitating the new and/or revised rejections set forth below.
New or Revised Claim Rejections Necessitated by Applicant Amendments
Claim Rejections - 35 USC § 112(b)
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 10, 14, 22-23, and 27-32 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.
Amended claims 10, 14, and newly added claims 22-23 and 27-32, all recite “wherein” clauses that render the claim scope indefinite. In brief,
it is uncertain if the “wherein” clauses should be interpreted as functional limitations further limiting the scope of the claim upon which these claims depend, or if the “wherein” clauses are non-limiting recitations of intended and expected results fully satisfied by all polypeptide structures satisfying the limitations set forth in the body of amended claim 1 1 (i.e., any polypeptide “having an amino acid sequence as set forth in SEQ ID NO: 2 or SEQ ID NO: 4, wherein the polypeptide comprises a substitution at the amino acid position of D291 of SEQ ID NO: 2”); and
if the “wherein” clauses are functional limitations that further limit the scope of claim 1 (or the claim upon which the claim depends) by excluding some, but not all embodiments within that claim, it is unknown what embodiments do or do not satisfy such functional limitations in the absence of a structure/function relationship.
This impacts the scope of the claim because, currently, at least the following sequences satisfy the positively recited structural limitations of instant claim 1: (a) SEQ ID NO: 2 having a D291E substitution; (b) SEQ ID NO: 2 having a D291S substitution; (c) SEQ ID NO: 2 having a D291F substitution; (d) SEQ ID NO: 2 having a D291G substitution; (e) SEQ ID NO: 2 having a D291dC substitution4; (f) SEQ ID NO: 2 having a D291βA substitution5; etc. Accordingly, if such limitations are not limiting (see, e.g., MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not limit a claim to a particular structure”, noting that the “wherein” clauses fail to correspond to any structure/function limitation), all of these structures (a)-(f), etc. would read upon all of claims 1, 10, 14, 22-23, and 27-32. Alternatively, if the “wherein” clauses constitute functional limitations corresponding to an unknown structure/function requirement, then structure (a) might satisfy claim 10 but not claim 22 or claim 27; and likewise, the structure (f) might satisfy claim 22 but not claim 10; likewise, structure (a) might satisfy all of the “wherein” clause limitations, but structure (d) may satisfy none of them. Accordingly, even if such “wherein” clauses are meant to be functional limitations, the claims would remain indefinite because no meaningful guidance is provided on record for reasonably distinguishing infringing from non-infringing embodiments. This is pertinent because
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.”
University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
(see also MPEP § 2173, explaining that “The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent”). Accordingly, claims 10, 14, 22-23, and 27-32 are indefinite because it is unclear if the “wherein” clauses are limiting or merely recitations of intended and expected results satisfied by all embodiments within the scope of instant claim 1. For purposes of applying prior art under 35 USC §102 and §103, the “wherein” clauses are reasonably inferred to correspond to recitations of intended and expected results fully satisfied by all polypeptides that satisfy the structurally complete limitations set forth in the body of amended claim 1 (i.e., any polypeptide “having an amino acid sequence as set forth in SEQ ID NO: 2 or SEQ ID NO: 4, wherein the polypeptide comprises a substitution at the amino acid position of D291 of SEQ ID NO: 2”). This interpretation is reasonable because the “wherein” clauses do not appear to correspond to any meaningful functional limitations of record since no structure/function relationship commensurate in scope with such limitations and claim scope exists on record (see also MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that . . . . does not limit a claim to a particular structure”).
Claims 30-31 recite the limitation "composition" at line 1 of each claim. There is insufficient antecedent basis for this limitation in the claim. For purposes of applying prior art, it is reasonably inferred that such claims depend from claim 10.
Accordingly, claims 10, 14, 22-23, and 27-32 are rejected.
Claim Rejections - 35 USC § 112(a), Written Description
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 10, 14, 22-23, and 27-32 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.
Claim Scope and Statement of the Issue(s)
Amended claim 1 encompasses >>100,000 trillion species6, wherein such species may or may not be functional at all. Now, amended claims 10, 14, 22-23, and 27-32 each recite a “wherein” clause, which is presumed for purposes of the instant rejection to be functional limitations presumably including some species within the scope of instant claim 1, while excluding other species within the scope of claim 1. However, the “wherein” clauses at 10, 14, 22-23, and 27-32 fail to meaningfully refer to a any structure/function relationship of record or known in the prior art, which raises substantial written description concerns, because it is unclear what structures do or do not satisfy such functional limitations in view of the originally filed disclosure.
Accordingly, it is unclear if claims 10, 14, 22-23, and 27-32 each encompass >>trillions of species of polypeptides and compositions, or perhaps only ~10 or fewer species.
Lack of literal Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163.
No literal support exists for newly amended or newly added claims 10, 14, 22-23, and 27-32, which are each understood to potentially recite functional limitations that do not correspond to any literal disclosure of record.
Accordingly, if directed to subgenera of products defined by functional limitations at the “wherein” clauses, then claims 10, 14, 22-23, and 27-32 each lack literal support in the originally filed disclosure.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163. As noted above, the claims are not literally supported by the originally filed disclosure. Accordingly, the relevant issue is whether or not the new amendments and resulting claim scope is implicitly or inherently supported by the originally filed disclosure.
Zero structure/function relationships permitting artisans to identify structures within the scope of instant claim 1 that do or do not satisfy the functional limitations in the “wherein” clause appear in the originally filed disclosure.
The closest supporting disclosures, and why such disclosures are insufficient to establish literal, inherent, or implicit support commensurate in scope with instant claims 10, 14, 22-23, and 27-32 are discussed below.
Actual Reduction to Practice
A single species within the scope of instant claim 1 was reduced to practice, namely the species of D291N as shown at Table 2, which is shown to have reduced activity relative to instant SEQ ID NO: 2 (see, e.g., Spec. filed 5/08/2025 at Table 2 on p. 38, p. 37 at line 10 to p. 38 at line 10).
Zero species within the scope of instant claim 1 was shown having any improved activity relative to SEQ ID NO: 2 were reduced to practice in the originally filed disclosure (see id).
Zero species having a mutation at D291 as required by amended claim 1, and having any other additional mutation at any other position were actually tested, reduced to practice, or shown to have any activity.
Zero species having a D-amino acid or non-naturally occurring amino acid were tested or shown to have any activity.
Zero species reading upon amended claim 1 were reduced to practice and shown to actually satisfy any functional limitation set forth in the “wherein” clauses of instant claims 10, 14, 22-23, and 27-32.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In this case, the claims ostensibly encompass potentially >>100,000 trillion species as explained above, and are therefore understood be highly variable. As noted above, at best, only one disclosed species (i.e., SEQ ID NO: 2 having a D291N mutation, sharing ~99.87% identity or 711/712 positions with SEQ ID NO: 2) was tested and reduced to practice at all, and it was shown to have reduced activity relative to wild type (SEQ ID NO: 2). Zero species having any improvement relative to SEQ ID NO: 2 were reduced to practice or disclosed with specificity in the originally filed disclosure.
Therefore, the relevant issue is whether or not a single species of D291N is “representative” of >>trillions of species. Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, here, the disclosure of one species (and potentially zero species for some functional limitations) of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus. Furthermore, the disclosure of zero double, triple, etc. mutants does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The relevant issue is whether or not an artisan could identify a structure/function relationship permitting artisans to identify what species did or did not satisfy each functional limitation recited at instant claims 10, 14, 22-23, and 27-32.
Claims 10, 14, 22-23, and 27-32, all recite “wherein” clauses that lack written description support because such limitations fail to correspond to any specific structure/function relationships of record, commensurate in scope with instant claim 1, that is literally, inherently, or implicitly supported by the originally filed disclosure.
As an initial matter, an artisan reviewing the disclosure would assume conservative substitutions would not meaningfully alter the activity of the polypeptides relative to SEQ ID NO: 2 because the Specification literally discusses conservative substitutions and concludes that
[O]ne can make . . conservative amino acid changes in the parent polypeptide sequence with the expectation that the resulting polypeptides would have a similar or improved profile…
(see, e.g., Spec. filed 5/08/2023 at 34 at lines 5-13, 35 at lines 9-14).
However, in contrast to this general statement, the Specification provides evidence that the only tested embodiment within the scope of amended claim 1, having a single mutation, results in a mutant with substantially reduced activity relative to wild type (see, e.g., Spec. filed 5/08/2025 at Table 2 on p. 38, p. 37 at line 10 to p. 38 at line 10, noting that a D291N mutant of SEQ ID NO: 2, at Table 2, is shown to have reduced activity relative to instant SEQ ID NO: 2).
Accordingly, the conclusory statement regarding an “improved profile”7 is a conclusory and unsubstantiated claim in the originally filed disclosure, which is actually contradicted by all supporting evidence set forth in the originally filed disclosure. Accordingly, an artisan would not reasonably conclude that Applicant possessed any embodiments within the scope of amended claim 1 having “improved” activity, and would at best conclude that Applicant possessed only variants having similar or worse activity relative to SEQ ID NO: 2 (wild type) at the time of filing. Accordingly, such limited disclosure and failure to provide clear guidance regarding such variants of SEQ ID NO: 2 and the functional limitations set forth in the instant “wherein” clauses of claims 10, 14, 22-23, and 27-32, would not reasonably inform artisans of how to distinguish among structures that did or did not infringe upon such functional claim limitations.
Therefore, an artisan would not be reasonably apprised of whether a particular species within the scope of amended claim 1 read upon all, some, or none of the functional limitations set forth at claims 10, 14, 22-23, and 27-32. For example, at least the following sequences satisfy the positively recited structural limitations of instant claim 1:
(a) SEQ ID NO: 2 having a D291E substitution;
(b) SEQ ID NO: 2 having a D291S substitution;
(c) SEQ ID NO: 2 having a D291F substitution;
(d) SEQ ID NO: 2 having a D291G substitution;
(e) SEQ ID NO: 2 having a D291dC substitution8;
(f) SEQ ID NO: 2 having a D291βA substitution9; and
(g) A 5-mer fragment of SEQ ID NO: 2 comprising a substitution relative to D291 (and potentially other positions as no minimal sequence identity with SEQ ID NO: 2 is required, and no minimal fragment length is required)10.
Zero structure/function relationships corresponding to the metes and bounds of structures satisfying the functional limitations at issue has been provided on record permitting an artisan to identify infringing and non-infringing structures. Accordingly, if each “wherein” clause is a functional limitation, then in the absence of a structure/function relationship, it is prima facie unknown if all, some, or none of these exemplified sequences satisfy the limitation of individual claim 10, 14, 22, 23, 27, 28, 29, 30, 31, or 32. This is pertinent because the courts have stated that
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.”
University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, in the absence of guidance commensurate in scope with the “wherein” clauses and also the scope of amended claim 1, an artisan would not be able to distinguish among infringing or non-infringing embodiments.
Accordingly, the potential functional limitations at the amended claims raise a basic threshold question that is not answered on record, or by the prior art of record, namely “what structures do or do not satisfy the functional limitations at claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32?” The instant disclosure provides no clear guidance, but rather attempts to draw a fence around potentially trillions of species of variants of SEQ ID NO: 2 by providing a laundry list of potential substitutions and changes to SEQ ID NO: 2, including substitutions broadly including both L- and D-amino acids, and numerous “non-naturally occurring or non-standard synthetic amino acids” (see, e.g., Spec. filed 5/08/2025 at 33 at lines 10-16, p. 34 at lines 5 to p. 36 at line 31), at multiple positions (see, e.g., Spec. filed 5/08/2025 at 29 at lines 1-18), but fails to provide a structure/function relationship. However, this laundry list disclosure is unsupported by the record, which evidences only possession of a single species of SEQ ID NO: 1 having a single mutation at D291, which had substantially reduced activity relative to SEQ ID NO: 2 (see, e.g., Spec. filed 5/08/2025 at Table 2, p. 37 at line 10 to p. 38 at line 10).
In sum, the originally filed disclosure fails to reasonably inform artisans of what structures within the scope of amended claim 1 do or do not satisfy the functional limitations of instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32. Rather, Applicant has attempted to draw a fence around subject matter they hope and desire to achieve by providing, at best, vague and generic guidance, without actually informing artisans of what structures are within or outside the functionally defined subgenus. Accordingly, in the originally filed disclosure, Applicant has identified structures that they hope and desire to claim, encompassing >>trillions of species, but simply left it up to future researchers to “figure out” and newly discover which species actually satisfy the functional limitations and which do not.
Applicant Identified Support for Functional Limitations
Applicant alleges that support if found for the newly added and amended claim scopes at paragraphs [0018]-[0021], [0024]-[0027], [0028]-[0032], [0062], [0175]-[0180], [0181]-[0182], Table 2, and Figs. 2, 3, and 5 “of the specification as filed” (see Reply filed 3/05/2026 at 6 at 1st ¶ to page 7 at 1st partial ¶). The Application as-filed lacked paragraph numbers, and therefore it is understood that the Applicant is referring to the PG Publication of the instant Application. Regarding instant Figures 2, 3, and 5, these figures pertain to an unclaimed species, excluded from the pending claim scope (i.e., CAase, or SEQ ID NO: 2), and therefore do not provide support for the amended claim scope. Regarding paragraphs [0018]-[0021], [0028]-[0032], these paragraphs do not recite, disclose, or pertain to functional “wherein” clauses, and fail to identify any species within the scope of instant claim 1 that satisfy (or do not satisfy) the functional limitations as recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32. Regarding paragraphs [0024]-[0027], these paragraphs summarize Figures 4-7, but Figures 4-7 fail to pertain to any species within the scope of instant claim 1. Rather, such data is limited to CAase, (SEQ ID NO: 2). Accordingly, such disclosures fail to evidence possession of any species within the scope of instant claim 1 that is capable of satisfying the functional limitations recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32. Regarding paragraph [0062], this paragraph merely recites and defines what constitutes a conservative substitution; but no limitations requiring conservative substitutions is currently pending, and no structure/function relationships commensurate with the functional limitations of claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32 is defined on record to necessarily and inherently require conservative substitutions. Regarding paragraphs [0175]-[0180], these paragraphs do not recite, disclose, or pertain to functional “wherein” clauses, and fail to identify any species within the scope of instant claim 1 that satisfy (or do not satisfy) the functional limitations as recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32. At best, these disclosures pertain to >trillions of potential variants of SEQ ID NO: 2 and SEQ ID NO: 4, which is a laundry list disclosure that fails to actually identify what variants do or do not actually satisfy the functional limitations recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32. Regarding paragraphs [0181]-[0182], these paragraphs do not recite, disclose, or pertain to functional “wherein” clauses, and fail to identify any species within the scope of instant claim 1 that satisfy (or do not satisfy) the functional limitations as recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32. Rather, [0181] merely identifies that “one can make the following isosteric and/or conservative amino acid changes in the parent polypeptide sequence with the expectation that the resulting polypeptides would have a similar or improved profile”, and [0182] pertains specifically to “isosteric and/or conservative amino acid changes” for “alkyl-substituted hydrophobic amino acids”, but these are not pertinent to D291, because “D” (Aspartic Acid/Aspartate) is not an “alkyl-substituted hydrophobic amino acids” identified at [0182], and therefore such D291 mutations would not be considered “isosteric and/or conservative amino acid changes”. Accordingly, [0182] appears to have no clear relationship to the pending claim limitations. Regarding Table 2, Table 2 has been considered fully above, and discloses a single species within the scope of instant claim 1 that was reported to have substantially reduced activity relative to wild type (see, e.g., Spec. filed 5/08/2025 at Table 2 on p. 38, p. 37 at line 10 to p. 38 at line 10, noting that a D291N mutant of SEQ ID NO: 2, at Table 2, is shown to have reduced activity relative to instant SEQ ID NO: 2). However, Table 2 fails to literally, inherently, or implicitly disclose subgenera of instant claim 1 capable of satisfying the “wherein” clauses of instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32, if such “wherein” clauses are functional limitations.
Applicant also alleges post-filed data presented in a Declaration submitted November 12, 2025, evidences “actual reduction to practice” (see Reply filed 3/05/2026 at 7 at 1st partial ¶). This is incorrect because support commensurate in scope with the requirements of 35 USC 112(a) must be present in the originally filed disclosure, at the time of filing. Here, the Declaration was submitted years after filing and was not part of the originally filed disclosure. Accordingly, such arguments are not persuasive because they fail to reflect the legal requirements of 35 USC §112(a).
In sum, at this time, Applicant has failed to identify any supporting disclosure providing literal, implicit, or inherent support for the subgenera of sequences within the scope of instant claim 1, which are defined and delineated by the functional limitations set forth at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32.
Predictability in the Art
Although the level of skill in the art is high, the predictability in the biochemical arts is low due to the complexity of biological systems, differences in neighboring effects of mutations, concentration effects, formulation effects, etc. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance, the minimal, common structures, of any compound satisfying the functional limitations set forth at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32.
At best, an artisan would reasonably assume that variants of SEQ ID NO: 1 sharing >99% sequence identity and differing by a single conservative substitution would not substantially alter the performance and activities of instant SEQ ID NO: 2 in view of the prior art, because
In the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution (‘the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.’ Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989))”).
See MPEP § 2144.08(II)(A)(4)(c), emphasis added.
Accordingly, at best an artisan would assume species of SEQ ID NO: 2 having a single, conservative substitution would have essentially identical activity relative to SEQ ID NO: 2, but would not expect or predict that such conservative substitutions would yield significantly “improved” profiles. To this end, the instant Action separately considers and examines a species having a single, conservative substitution of instant SEQ ID NO: 2, based upon the assumption that it would merely yield the same activity as SEQ ID NO: 2 (see rejection(s) under 103, below, utilizing an alternative interpretation of the “wherein” clauses).
Accordingly, in the absence of sufficient structure/function teachings identifying which, if any, species of claim 1 actually satisfy the functional limitations of instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32, an artisan would not reasonably conclude Applicant had possession of such specialized subgenera of sequences since such functional limitations are not literally, inherently, or implicitly disclosed on record as corresponding to any particular structures within the scope of instant claim 1.
Conclusion
Per MPEP § 2163, new or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement (see, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971)). Here, the newly added claim limitations are not inherently, implicitly, or literally supported by the originally filed disclosure.
The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). Likewise, here zero evidence of any functional species having less than 711/712 residues in common with instant SEQ ID NO: 2 was provided in the originally filed disclosure; and zero evidence of any species within the scope of amended claim 1 being capable of actually satisfying the functional limitations presumably set forth at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32 was identified, taught, or exemplified on record. Accordingly, the claims attempt to draw a fence around potentially trillions of variants of the naturally occurring polypeptide of instant SEQ ID NO: 2, or possible only ten or fewer species, by attempting to functionally define subgenera of species capable of satisfying novel functional limitations, but the disclosure fails to actually establish the metes and bounds of any such structure/function relationship that would reasonably permit an artisan to reasonably conclude Applicant possessed such a subgenus of SEQ ID NO: 2 variants, or otherwise meaningfully identify/distinguish infringing and non-infringing embodiments.
Accordingly, claims 10, 14, 22-23, and 27-32 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 9-10, 14, 22-23, and 27-32 are rejected under 35 U.S.C. 103 as being unpatentable over NCBI GenBank: ADP02444.111 in view of US2019/0336551A1 (cited in previous action).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section and/or rejection, and those interpretations are incorporated herein. For purposes of the instant rejection, the “wherein” clauses at dependent claims 10, 14, 22-23, and 27-32 are presumed to be fully satisfied by all structures satisfying the structural limitations of instant claim 1, including variants of SEQ ID NO: 2 sharing >99.85% sequence identity and differing from SEQ ID NO: 2 by a single, conservative substitution at position D291.
Regarding instant claims 1, 9-10, 14, 22-23, and 27-32, ADP02444.1 discloses that instant SEQ ID NO: 2 is a naturally-occurring sequence from Salmonella phage PVPSE1 (compare ADP02444.1 with instant SEQ ID NO: 2, showing 100% identity). Claim 1 encompasses variants of the naturally occurring protein differing at a single position, including conservative substitutions. Regarding instant claims 9-10, 14, and the presence of a “carrier”, in view of complete sequence of ADP02444.1, an artisan would readily and necessarily appreciate that the protein could be produced and studied in carrier solutions suitable for use in routine biochemical assays.
The naturally occurring polypeptide of ADP02444.1 differs from the claimed species of SEQ ID NO: 2 having a D291E mutation as follows: ADP02444.1 possesses an aspartate (D) at position 291 rather than a glutamate (E). Accordingly, ADP02444.1 lacks a D291E mutation.
The MPEP provides guidance applicable to determining the obviousness of compounds having close structural similarity at MPEP § 2144.08 and MPEP § 2144.09. Specifically, MPEP § 2144.09(I) identifies that “[a] prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities”
The naturally occurring protein shares substantial structural similarity with the claimed genus of polypeptides: ADP02444.1 differs by a single residue from among 712 total residues, and therefore shares over 99.85% sequence identity with claimed species (e.g., all D291 mutants), and therefore would be readily understood by an artisan to “have very close structural similarities” with the claimed invention (MPEP § 2144.09(I)).
The naturally occurring protein differs from the claimed species of D291E by a single conservative substitution: ADP02444.1 possesses an aspartate (D) at position 291 rather than a glutamate (E). US’551 is cited herein to establish the state of the art regarding “conservative substitutions”, and the predicted and expected outcome of making conservative substitutions in the protein arts. Specifically, US’551 explains that
Homologous amino acid residues have similar chemical-physical properties, for example, amino acids belonging to a same group: aromatic (Phe, Trp, Tyr), acid (Glu, Asp), polar (Gln, Asn), basic (Lys, Arg, His), aliphatic (Ala, Leu, Ile, Val), with a hydroxyl group (Ser, Thr), or with a short lateral chain (Gly, Ala, Ser, Thr, Met). It is expected that substitutions between such homologous amino acids do not change a protein phenotype (conservative substitutions).
(see, e.g., US’551 at ¶[0036], emphasis added).
Accordingly, aspartate (Asp, D) and glutamate (Glu, E) are art-recognized conservative substitutions for each other, and an artisan would not expect that a conservative substitution from (D) to (E) would alter the activity of a protein. This reflects the MPEP guidance at MPEP § 2144.08(II)(A)(4)(c), which explains that some differences may be “of little importance”, and identifies that
In the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution (‘the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.’ Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989))”).
See MPEP § 2144.08(II)(A)(4)(c), emphasis added.
Accordingly, a (D) to (E) mutation is an art-recognized conservative substitution, and therefore such change would be predicted to “lead to either no change or only a small change” absent objective evidence to the contrary.
The naturally occurring protein differs from the claimed species of D291E by a single -CH2- moiety: An artisan would appreciate that aspartate (D) and glutamate (E) are homologs differing by a single -CH2- moiety in the respective side chains of each amino acid. Accordingly, the difference between the claimed species of SEQ ID NO: 2 having a D291E and the prior art species of ADP02444.1 is understood to be a single -CH2- moiety over the entire structure. This is pertinent because MPEP § 2144.09(II) identifies that “Compounds which are . . . homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
The utility of the naturally occurring protein would be expected and predicted to be the same or otherwise highly similar, because the claimed species of D291E mutant differs from ADP02444.1 by a single -CH2- moiety: As noted above, aspartate (D) and glutamate (E) are homologs differing by a single -CH2- moiety in the respective side chains of each amino acid, and are art-recognized conservative substitutions for each other (see above). Accordingly, an artisan would have readily predicted and expected that mutants sharing substantial structural similarity with ADP02444.1 would also have the same predicted and expected utility as ADP02444.1 (see, e.g., US’551 at ¶[0036], quoted above; see also MPEP § 2144.08(II)(A)(4)(c) discussing conservative substitutions, quoted above).
Regarding motivation, it is routine in the protein arts to make single-position mutants of a known protein to study biological pathways, protein architecture, structure/function relationships, etc (i.e., one of ordinary skill in the protein arts would be well-aware of alanine-scanning assays, homolog-scanning assays, and mutational analysis). In addition, or alternatively, an artisan would be motivated to make single-position, conservative mutants of the naturally-occurring protein of ADP02444.1 in order to predictably obtain highly conservative variants “in the expectation that compounds similar in structure will have similar properties” (see, e.g., MPEP 2144.09(I); note that the expected activity would be “colonic acid biosysnthesis” as noted at ADP02444.1 at 1). In addition, or alternatively, an artisan would appreciate that naturally-occurring proteins (i.e., ADP02444.1) could not be directly patented because they are a judicial exception under 35 USC 101, and therefore would be motivated to attempt to essentially claim a naturally occurring protein by making minimal, trivial, or conservative changes to the naturally-occurring structure in the hope to circumvent 35 USC 101, while predictably preserving the functionality of the naturally-occurring protein (i.e., here “colonic acid biosynthesis”), and claiming highly similar sequences as routinely defined by reference to sequence identity.
Therefore, the relevant issue for determining obviousness of the pending claims is whether or not a mutant of the naturally-occurring protein of ADP02444.1 is obvious under 35 USC 103, wherein the mutant only differs from the natural protein by a single, conservative substitution (i.e., from an aspartate (D) to a glutamate (E)), wherein the naturally occurring protein differed from the claim scope by a single -CH2- moiety, and wherein the conservatively substituted mutant would have been predicted and expected by one of ordinary skill in the art to exhibit the same activity exhibited by the naturally-occurring protein of ADP02444.1 (i.e., “colonic acid biosynthesis”). Upon analysis of MPEP § 2144.09(I)-(II) and the prior art identified above, it is the Examiner’s position that it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, because MPEP § 2144.09 identifies that “[a] prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities”, and that homologs “are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties” (see, e.g., MPEP § 2144.09(I)-(II)), and here a conservative substitution of D291E shares over 98.85% identity with the naturally-occurring polypeptide, differing by a single -CH2-moiety, and would therefore be predicted and expected to have the exact same utility as ADP02444.1, wherein an artisan would be motivated to make conservative variants “in the expectation that compounds similar in structure will have similar properties” (see, e.g., MPEP 2144.09(I); see also MPEP § 2144.06(II)).
Per MPEP § 2144.09(VII), the instant rejection may be rebutted by evidence of unexpected results. Applicant is advised that evidence of unexpected results must be commensurate in scope with the requirements of MPEP §§ 716, 716.01, or 716.02. To date, no such evidence has been placed on record. Applicant is advised that the closest existing prior art sequence is ADP02444.1.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to make conservative substitution variants of a known protein sequence using routine methods in the biochemical arts. Furthermore, MPEP § 2144.08(II)(A)(4)(c) explains that a conservative substitution is “the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.” Accordingly, the expected and predicted result of such changes would be “no change or only a small change” in properties.
Accordingly, claims 1, 9-10, 14, 22-23, and 27-32 are rejected.
Response to Arguments
Applicant's arguments filed 3/05/2026 have been fully considered but they are not persuasive. Examiner notes that arguments pertaining to withdrawn objections or rejections have been substantially rendered moot in view of the withdrawal of such rejections. Remaining applicable arguments to the new or revised rejections are addressed below.
Newly Added Claims
Although claims 20-21 and 24-25 are not presently considered, Applicant is advised that such claims do not appear to be supported by either the disclosure of US Provisional 63/018,951 or the originally filed disclosure.
Examiner notes that Applicant did not unambiguously identify where supporting disclosures for such claimed species (e.g., D291A) or subgenera (i.e., compounds having at least two substitutions, including a D291 substitution) appear in the originally filed disclosure (see, e.g., Reply filed 11/12/2025 at 5; see, e.g., Reply filed 3/05/2026 at 6-7). Applicant is advised that upon examination of such claims, such limitations will be considered under 35 USC § 112(a), and priority may be denied to such claims in a subsequent action.
Accordingly, to facilitate compact prosecution, Applicant is invited in a subsequent response to clearly identify supporting disclosures for these claims.
35 USC 112(b)
Applicant addresses prior rejections under 35 USC 112(b) premised upon the usage of “effective amount” at page 8 of the Reply (see, e.g., Reply filed 3/05/2026 at 8 at 1st and 2nd ¶¶). The prior rejection is withdrawn as moot. However, the amendments and newly added claims have necessitated new rejections under 35 USC 112(b) as set forth above.
35 USC 112(a)
Applicant addresses prior rejections under 35 USC 112(a) premised upon the usage of “effective amount” at pages 8-9 of the Reply (see, e.g., Reply filed 3/05/2026 at 8 at 3rd ¶ to 9 at 1st partial ¶). The prior rejection over claim 1 and 10 has been withdrawn as moot. However, the amendments and newly added claims have necessitated a new and revised rejection under 35 USC 112(a) as set forth above in view of newly added or amended claims 10, 14, 22-23, and 27-32.
Examiner acknowledges that Applicant has alleged that the pending and examined claims are supported by the disclosures at paragraphs [0018]-[0021], [0024]-[0027], [0028]-[0032], [0062], [0175]-[0180], [0181]-[0182], Table 2, and Figs. 2, 3, and 5 “of the specification as filed” (see Reply filed 3/05/2026 at 6 at 1st ¶ to page 7 at 1st partial ¶). The Application as-filed lacked paragraph numbers, and therefore it is understood that the Applicant is referring to the PG Publication of the instant Application. Regarding these disclosures:
Regarding instant Figures 2, 3, and 5, these figures pertain to an unclaimed species, excluded from the pending claim scope (i.e., CAase, or SEQ ID NO: 2), and therefore do not provide support for the amended claim scope.
Regarding paragraphs [0018]-[0021], [0028]-[0032], these paragraphs do not recite, disclose, or pertain to functional “wherein” clauses, and fail to identify any species within the scope of instant claim 1 that satisfy (or do not satisfy) the functional limitations as recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32.
Regarding paragraphs [0024]-[0027], these paragraphs summarize Figures 4-7, but Figures 4-7 fail to pertain to any species within the scope of instant claim 1. Rather, such data is limited to CAase, (SEQ ID NO: 2). Accordingly, such disclosures fail to evidence possession of any species within the scope of instant claim 1 that is capable of satisfying the functional limitations recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32.
Regarding paragraph [0062], this paragraph merely recites and defines what constitutes a conservative substitution; but no limitations requiring conservative substitutions is currently pending, and no structure/function relationships commensurate with the functional limitations of claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32 is defined on record to necessarily and inherently require conservative substitutions.
Regarding paragraphs [0175]-[0180], these paragraphs do not recite, disclose, or pertain to functional “wherein” clauses, and fail to identify any species within the scope of instant claim 1 that satisfy (or do not satisfy) the functional limitations as recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32. At best, these disclosures pertain to >trillions of potential variants of SEQ ID NO: 2 and SEQ ID NO: 4, which is a laundry list disclosure that fails to actually identify what variants do or do not actually satisfy the functional limitations recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32.
Regarding paragraphs [0181]-[0182], these paragraphs do not recite, disclose, or pertain to functional “wherein” clauses, and fail to identify any species within the scope of instant claim 1 that satisfy (or do not satisfy) the functional limitations as recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32. Rather, [0181] merely identifies that “one can make the following isosteric and/or conservative amino acid changes in the parent polypeptide sequence with the expectation that the resulting polypeptides would have a similar or improved profile”, and [0182] pertains specifically to “isosteric and/or conservative amino acid changes” for “alkyl-substituted hydrophobic amino acids”, but these are not pertinent to D291, because “D” (Aspartic Acid/Aspartate) is not an “alkyl-substituted hydrophobic amino acids” identified at [0182], and therefore such D291 mutations would not be considered “isosteric and/or conservative amino acid changes”. Accordingly, [0182] appears to have no clear relationship to the pending claim limitations.
Regarding Table 2, Table 2 has been considered fully above, and discloses a single species within the scope of instant claim 1 that was reported to have substantially reduced activity relative to wild type (see, e.g., Spec. filed 5/08/2025 at Table 2 on p. 38, p. 37 at line 10 to p. 38 at line 10, noting that a D291N mutant of SEQ ID NO: 2, at Table 2, is shown to have reduced activity relative to instant SEQ ID NO: 2). However, Table 2 fails to literally, inherently, or implicitly disclose subgenera of instant claim 1 capable of satisfying the “wherein” clauses of instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32, if such “wherein” clauses are functional limitations.
Accordingly, considered as a whole, such disclosures fail to literally, inherently, or implicitly disclosure the “wherein” clauses pertaining to any species within the scope of amended claim 1. At best, the D291N mutant at Table 2 would read upon claim 1, but there is zero literal, inherent, or implicit guidance suggesting that this species (or any other within the scope of claim 1) would satisfy the “wherein” clauses of recited at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32.
Applicant also alleges post-filed data presented in a Declaration submitted November 12, 2025, evidences “actual reduction to practice” (see Reply filed 3/05/2026 at 7 at 1st partial ¶). This is incorrect because support commensurate in scope with the requirements of 35 USC 112(a) must be present in the originally filed disclosure, at the time of filing. Here, the Declaration was submitted years after filing and was not part of the originally filed disclosure. Accordingly, such arguments are not persuasive because they fail to reflect the applicable legal requirements of establishing written description support commensurate in scope with 35 USC §112(a).
In sum, at this time, Applicant has failed to identify any supporting disclosures of record providing literal, implicit, or inherent support for any subgenera of sequences within the scope of instant claim 1, which are defined and delineated by the “wherein” clauses set forth at instant claims 10, 14, 22, 23, 27, 28, 29, 30, 31, and 32.
35 USC 103
It is the Examiner’s understanding that Applicant traverses the prior rejection of record in view of the amendments filed 3/05/2026 (see, e.g., Reply filed 3/05/2026 at 9 at 1st to 2nd full ¶¶). The rejection has been revised as necessitated by Applicant’s amendments and newly added claims.
Applicant provides a conclusory statement alleging that the rationales for supporting a determination of obviousness at MPEP § 2144.09(I)-(II) are “inapplicable where the claim is directed to a specific mutant differing at a specific residue known to affect activity”. The legal basis of this assertion is unknown and no MPEP or case law cite is provided supporting the Applicant’s conclusory statement. As explained in the rejection, the claim scope encompasses the species of D291E substituted SEQ ID NO: 2, which differs from the closest prior art of record by a single -CH2- moiety (see rejection, above). Critically, a difference of a single -CH2- moiety is an explicitly addressed and exemplified case of homologous structures identified at MPEP § 2144.09(II) as supporting a prima facie determination of obviousness. Accordingly, the Examiner’s position is that MPEP § 2144.09(I)-(II) are applicable, and support a determination of prima facie obviousness of the pending claim scope, which differs from the closest prior art by a single -CH2- moiety and conservative amino acid substitution, and zero evidence of unexpected results commensurate in scope with the pending claims has been placed on record rebutting the rejection as set forth at MPEP § 2144.09(V).
Applicant alleges that the evidence of record establishes that mutations to position D291 impact activity (see, e.g., Reply filed 3/05/2026 at 9 at 2nd full ¶¶) as evidenced by the D291N mutation tested at Table 2 (see id). This is not persuasive as follows:
First, Table 2 lacks error bars and is therefore of unknown statistical significance, and therefore the data shows an expected result, namely that a conservative substitution leads to similar activity, which is evidence of obviousness rather than non-obviousness since retained and similar activity is the expected result (see, e.g., MPEP § 716.02(c)(II), noting that "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof”).
Second, the examined species is a D291E substitution, which is more conservative than the tested D291N substitution because D and E are both negatively charged and differ by a single -CH2- moiety, wherein a D to N substitution requires changing a charged residue (D) to a polar but uncharged one (N) that includes an additional functional moiety. Therefore, the data pertaining to D291N does not alter the predicted and expected results of conservative substitutions (see, e.g., MPEP § 2144.08(II)(A)(4)(c)12).
Third, Applicant’s argument appears to contradict the instant specification, which teaches that conservative substitutions are predictable (see, e.g., Spec. filed 5/08/2023 at 12 at line 25 to page 13 at line 2, page 34 at lines 5-12, page 35 at lines 9-14). Applicant’s own disclosure identifies that the substitution of acidic amino acids includes aspartic acid (D) to glutamic acid (E) (see, e.g., Spec. filed 5/08/2023 at page 35 at lines 9-14), which is identified as a conservative substitution, that “would have a similar or improved profile” relative to the original sequence (see, e.g., Spec. filed 5/08/2023 at page 34 at lines 5-12). Critically, Asparagine (N) and aspartic acid (D) is not identified as such a substitution (see, e.g., Spec. filed 5/08/2023 at page 35 at lines 9-15). Therefore, Applicant’s own specification reasonably suggests that a D291N and D291E variant of SEQ ID NO: 2 would differ, because D291E is identified as a conservative substitution that “would have a similar or improved profile” relative to the original sequence, but a D291N substitution is not (see, e.g., Spec. filed 5/08/2023 at page 34 at lines 5-12, page 35 at lines 9-15).
Fourth, if true, Applicant’s allegation regarding lack of predictability would actually weigh unfavorably against Applicant’s position, because it would suggest and support a lack of written description and lack of enablement commensurate in scope with the instant claims. Stated alternatively, Applicant cannot simultaneously maintain that untested species that were not specifically recited on record are both (i) sufficiently described to satisfy 35 USC 112(a) requirements because of disclosures pertaining to conservative substitutions (see Reply filed 3/05/2026 at 6 at 1st ¶ to page 7 at 1st partial ¶), but (ii) that prior art differing by a single conservative substitution does not render such claims obvious due to lack of predictability of conservative substitutions. Such dual positions are incongruent.
Accordingly, such arguments have been fully considered but not found persuasive because such arguments amount to a dismissal of the cited evidence, MPEP citations, and legal citations provided by the Examiner supporting a determination of obviousness.
Examiner previously considered the Declaration filed 11/12/2025 and explained how it failed to support a determination of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, or 716.02 (see, e.g., Action mailed 12/05/2025 at 27-31), and Applicant fails to acknowledge or address the Examiner’s analysis or determinations of record. This is pertinent because Examiner noted that the evidence of record set forth in the Declaration (see Reply filed 11/12/2025 at 6-7 at §(4); see Berger Declaration filed 11/12/2025) weighed in favor of a determination of obviousness:
The proffered evidence of record set forth in the Declaration (see Reply filed 11/12/2025 at 6-7 at §(4); see Berger Declaration filed 11/12/2025) weighed in favor of a determination of obviousness because it provided a test between Wild-type (i.e., SEQ ID NO: 2) (the closest prior art of record) and a D291A mutant of SEQ ID NO: 1, but shows evidence that the tested species does not have activity that is “greater than expected” because the WT is shown to have more activity at Figures 1-2 of the Dec; therefore, this data does not satisfy MPEP § 716.02(a)(I).
The proffered data in the Declaration failed to identify any “superiority of a property” (see, e.g., MPEP § 716.02(b)(I), noting that the burden is on the Declarant to explain proffered data) and therefore the proffered data did not satisfy MPEP § 716.02(a)(II). In addition, the evidence showed reduced activity at Figures 1-2, but did not show any new or “unexpected property” or an “absence of an expected property”, and therefore such data does not clearly satisfy either MPEP § 716.02(a)(III) or § 716.02(a)(IV). In sum, the proffered data appears to not show evidence required by MPEP § 716.02(a), but instead shows that a non-conservative substitution reduced activity, which would be the expected result. Declarant failed to actually explain why an artisan would assume a non-conservative substitution would not alter enzymatic activity, which does not appear to be surprising or unexpected.
As explained in the prior Action, per MPEP § 716.02(b)(I), the burden is on the Declarant to establish that results are “in fact unexpected and unobvious and of both statistical and practical significance”. However, the Declarant failed to provide an explanation of the practical significance of a D291A mutant that appears to perform worse and have reduced activity relative to wild-type. It remains unknown and unexplained on record why decreased activity would be desirable or practically significant because the Declarant explained that such polypeptides are intended for use as enzymatic disinfectants (see, e.g., Declaration at ¶¶6). Accordingly, a discovery of how to reduce such activity appears to lack a clear practical significance since such result would presumably reduce the ability of such peptides to act as enzymatic disinfectants, thereby rendering them less suitable for their intended purpose.
As noted in the prior Action, per MPEP § 716.02(c)(II), "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." Here, the predicted and expected results in view of the prior art is that a conservatively-substituted variant of the naturally occurring ADP02444.1 protein would have the same or highly similar utility as ADP02444.1. The proffered data set forth in the Declaration did not disprove or challenge this expectation. Rather, as noted above, the data merely shows that a non-conservative substitution reduces activity, and fails to rebut the predicted and expected results of conservative substitutions.
As noted in the prior Action, Declarant provided zero scientific or experimental rationales for reasonably extending the data at Figures 1-2 of the Declaration to the full scope of claimed species at instant claim 1, including conservative substitutions of ADP02444.1 (see, e.g., MPEP § 716.02(b)(I), noting that the burden is on the Declarant to explain proffered data). The art teaches that conservative substitutions are expected to perform differently than non-conservative mutations (see, e.g., US’551 at ¶[0036], quoted above; see also MPEP § 2144.08(II)(A)(4)(c) discussing conservative substitutions, quoted above); and therefore, absent evidence that non-conservative and conservative mutations are reasonably represented by a single alanine substitution, such data cannot reasonably be said to satisfy the requirement of MPEP § 716.02(d). Alternatively, assuming arguendo that the proffered data with D291A was extended to all possible D291 mutants, the proffered data would suggest such variants of SEQ ID NO:2 would not show improved or new properties, or a lack of existing properties (see, e.g., MPEP § 716.02(a)(III) or § 716.02(a)(IV)), which weighs against a determination of unexpected results.
Accordingly, data directed to non-conservative substitutions do not reasonably address the predictability and expectations of conservatively substituted variants within the scope of instant claim 1. Therefore, zero data of record suggests or establishes that conservatively substituted species within the scope of instant claim 1 exhibit any improved or unexpected properties relative to the closest prior art of record. Examiner notes that all determinations not specifically addressed and disputed by the Applicant are understood to be undisputed on the instant record.
To date, no evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, or 716.02 has been placed on record to date. Specifically, no evidence showing a difference “of both statistical and practical significance” (see, e.g., MPEP § 716.02(b)) has been placed on record commensurate in scope with the pending claim scope (see, e.g., MPEP § 716.02(d)), relative to the closest, existing prior art of record (see, e.g., MPEP § 716.02(e)).
Accordingly, the claimed invention remains rejected as obvious in view of the revised rejection above, wherein all revisions were necessitated by Applicant amendment.
Conclusion
All applicable arguments raised by the Applicant have been fully considered but not found persuasive for the reasons discussed above. Accordingly, the claims are rejected for reasons set forth above in the new or revised rejections. All new or revised rejections were necessitated by Applicant’s amendments.
Examination has not yet proceeded beyond the originally elected species and the non-elected species of SEQ ID NO: 2 having a D291E substitution.
Pertinent Prior Art and Examiner Notes
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wingfield et al. (Overview of the purification of recombinant proteins. Curr Protoc Protein Sci. 2015 Apr 1;80:6.1.1-6.1.35. doi: 10.1002/0471140864.ps0601s80. PMID: 25829302; PMCID: PMC4410719; hereafter “Wingfield”; cited in previous action), covers the basic, routine protocols utilized in the art to recombinantly express and purify prior art proteins (see, e.g., Wingfield, passim). This is pertinent because it is routine in the art to take known proteins, recombinantly express them in a suitable host, purify the protein following lysis of the host cell, isolate the protein of interest in a carrier, and to concentrate the protein to a desired concentration suitable for a particular application (see, e.g., Wingfield, passim).
Livingstone et al.13. pertains to conservative substitutions known in the prior art (see, e.g., Livingstone at Fig 1(a)-(b) on page 747).
Santos et al.14 taught and disclosed compositions comprising the naturally occurring polypeptide associated with Accession no. GU070616 (see, e.g., Santos at 11266 at col I at 7th ¶). As shown by ADP02444.1 (see, e.g., ADP02444.1 at 1 at “DBSOURCE” and “CDS”, referring to GU070616.1, see also id. at 1 at “Reference 1” referring to Santos), Santos disclosed, tested, and identified compositions comprising instant SEQ ID NO: 2 (compare ADP02444.1 with instant SEQ ID NO: 2, showing 100% identity). The naturally occurring protein was discovered in a German wastewater plant (see, e.g., Santos at abs, 11269 at Table 1 at gp49, 11270 at col I-II at bridging ¶; see, e.g., ADP02444.1 at page 1 at “Reference 1” identifying the Santos reference). Santos reported that such myovirus has a “broad lytic spectrum against different Salmonella strains” (see, e.g., Santos at abs). Santos teaches that the protein of ADP02444.1 was discovered existing in wastewater (see, e.g., Santos at abs), and was identified using phage particles (see, e.g., Santos at 11265 at col II at § “Phage purification”; at 11265 at col II at § “Phage infection”), wherein Santos identifies that compositions comprising all of the proteins of Salmonella myovirus PVP-SE1 were grown in a carrier (see, e.g., Santos at 11265 at col II at § “Phage purification”) and additionally identifies that compositions comprising the PVP-SE1 structural proteins were reduced to practice in carrier solutions suitable for use in proteomic analysis assays (see, e.g., Santos at 11266 at col II at § Proteomic analysis). Santos discloses compositions comprising the protein of ADP02444.1, wherein the compositions have a pH of 7.5 (see, e.g., Santos at 11265 at col II at § “Phage purification”), and a pH of 4.5 and pH of 7.0 (see also id. at 11265 at col II at § “Transmission electron microscopy”).
Heydenreich et al.( High-throughput Site-directed Scanning Mutagenesis Using a Two-fragment PCR Approach. Bio Protoc. 2020 Jan 5;10(1):e3484. doi: 10.21769/BioProtoc.3484. PMID: 33654716; PMCID: PMC7842796) pertains to high-throughput site-directed scanning mutagenesis techniques (see, e.g., Heydenreich at title, abs), which establishes that high-throughput alanine scanning to create libraries of hundreds of single-point mutations permitting “complete coverage” of a protein sequence was known and routine in the prior art. Accordingly, alanine mutants are the result of routine alanine-scanning in the prior art.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 Claim 12 was inadvertently grouped with “polypeptides”, but depends from claim 7 of Group II (polynucleotides) and correctly belongs with Group II.
2 Santos et al., Genomic and proteomic characterization of the broad-host-range Salmonella phage PVP-SE1: creation of a new phage genus. J Virol. 2011 Nov;85(21):11265-73. doi: 10.1128/JVI.01769-10. Epub 2011 Aug 24. PMID: 21865376; PMCID: PMC3194984; hereafter “Santos”; cited in previous action.
3 NCBI GenBank: ADP02444.1, putative fusion protein [Salmonella phage PVPSE1], PHG 12-Oct-2011, attached as 2 page pdf, also available at https://www.ncbi.nlm.nih.gov/protein/ADP02444.1?report=genbank&log$=protalign&blast_rank=1&RID=E1P4RNBH013 (last visited 9/11/2024); hereafter “ADP02444.1”; cited in previous action.
4 Wherein “dC” is D-Cys (see, e.g., Spec. filed 5/08/2023 at 33 at line 29 to 34 at line 4).
5 Wherein “βA” is Beta-alanine (see, e.g., Spec. filed 5/08/2023 at 33 at line 10-16).
6 I.e., as explained in the claim interpretation section above, claim 1 reads upon fragments of instant SEQ ID NO: 2 and 4 (e.g., tripeptides, 10-mers, etc.), and include D-amino acid variants and non-naturally occurring polypeptides. Amended claim 1 requires no minimal sequence length so long as the compound is a “polypeptide” within instant SEQ ID NO: 2, and comprises a substitution at a position relative to D291. Instant claim 21 evidences that no minimal sequence identity relative to SEQ ID NOs: 2 or 4 is required by instant claim 1. As noted in the Specification, each position is not limited to the 20 proteinogenic amino acids, but instead broadly includes D-amino acids, and “non-naturally occurring or non-standard synthetic amino acids” (see, e.g., Spec. filed 5/08/2025 at 33 at lines 10-16, p. 34 at lines 5 to p. 36 at line 31). Accordingly, the scope of claim 1 encompasses trillions of species of peptides that are not required to share any consensus structure.
7 see, e.g., Spec. filed 5/08/2023 at 34 at lines 5-13, 35 at lines 9-14.
8 Wherein “dC” is D-Cys (see, e.g., Spec. filed 5/08/2023 at 33 at line 29 to 34 at line 4).
9 Wherein “βA” is Beta-alanine (see, e.g., Spec. filed 5/08/2023 at 33 at line 10-16).
10 See claim interpretation regarding definite and indefinite articles used with SEQ ID NOs.
11 NCBI GenBank: ADP02444.1, putative fusion protein [Salmonella phage PVPSE1], PHG 12-Oct-2011, attached as 2 page pdf, also available at https://www.ncbi.nlm.nih.gov/protein/ADP02444.1?report=genbank&log$=protalign&blast_rank=1&RID=E1P4RNBH013 (last visited 9/11/2024); hereafter “ADP02444.1”; cited in previous action.
12 “In the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution (‘the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.’ Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989))”).
See MPEP § 2144.08(II)(A)(4)(c), emphasis added.
13 Livingstone et al. (Protein sequence alignments: a strategy for the hierarchical analysis of residue conservation. Comput Appl Biosci. 1993 Dec;9(6):745-56. doi: 10.1093/bioinformatics/9.6.745. PMID: 8143162; cited in previous action).
14 Santos et al., Genomic and proteomic characterization of the broad-host-range Salmonella phage PVP-SE1: creation of a new phage genus. J Virol. 2011 Nov;85(21):11265-73. doi: 10.1128/JVI.01769-10. Epub 2011 Aug 24. PMID: 21865376; PMCID: PMC3194984; hereafter “Santos”; cited in previous action.
Prosecution Insights