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 .
Election/Restrictions
Claims 16-25, 29, 30, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or non-elected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/2025.
Applicant’s election of Group 1 (host cell) and OPNA hydrolyzing enzyme species PTE, SEQ ID NO: 1, and N266G, and species V-agent in the reply filed on 12/19/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The examiner notes that the elected substitution to SEQ ID NO: 1, N266G, is represented by instant SEQ ID NO: 149. Claim 11 is newly amended to add the limitation “and/or wherein the PTE comprises a sequence that is at least 90% identical to any one of SEQ ID NOs: 36-795.” As such, based on the Applicant’s previous election, SEQ ID NO: 149 is also treated as an elected species for claim 11.
Claims 1-4, 10, 11, 15-25, 29, 30, and 48 are pending.
Claims 16-25, 29, 30, and 48 are withdrawn.
Claims 1-4, 10, 11, and 15 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application provisional application 63/176,183 filed on 4/16/20211 and PCT/US22/25011 filed 4/15/2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/04/2024 is considered by the examiner.
Drawings
The drawings filed 9/22/2023 are accepted.
Specification
The specification filed 9/22/2023 is accepted.
Claim Objections
Claim 1 is objected to because of the following informalities: The examiner recommends reciting “organophosphorus nerve agent (OPNA)” when first introducing “OPNA” in the claim.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites “a heterologous polynucleotide encoding an OPNA hydrolyzing enzyme, wherein the OPNA hydrolyzing enzyme is a phosphotriesterase (PTE) or a phosphotriesterase-related protein (PTER)”. “OPNA hydrolyzing” is interpreted to be a functional characteristic of the enzyme, and does not further limit the structure of the heterologous polynucleotide encoding the enzyme.
Claim 11 recites “one or more of the amino acid substitutions relative to the sequence of any one of “SEQ ID NOs: 1-4”, and claim 15 recites “one or more of the amino acid substitutions relative to SEQ ID NO: 1”. These recitations are interpreted to mean that one or more of the amino acids comprising SEQ ID NO: 1 is/are substituted.
Claim Rejections - 35 USC § 112(a)- Written Description
Claims 2 and 15 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 2 recites “wherein the PTE or PTER comprises the sequence of any one of SEQ ID NOs: 1-4, 6, and 9” (SEQ ID NO:1 elected species).
Claim 15 recites “wherein the PTE has activity against VX and VR and wherein the PTE comprises one or more of the following amino acid substitutions relative to SEQ ID NO: 1:…”
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Currently, claim 2 requires an OPNA hydrolyzing enzyme comprising 100% of SEQ ID NO: 1 (i.e., no modifications or substitutions).
Additionally, claim 15 recites 22 different amino acid positions that may be modified in SEQ ID NO: 1. As written, claim 15 indicates that any combination or number of (including up to all 22 positions) amino acid substitutions can be made to SEQ ID NO: 1 at the same time and still maintain the same function. Depending on the position, the amino acid may be substituted with a single other amino acid (e.g., V25), or five other amino acids (e.g., N266), for example. As such, a vast number of modifications to SEQ ID NO:1 as encompassed by the claim language.
The working examples do not show the activity of SEQ ID NO: 1 with no modifications.
The working examples of the instant specification (e.g., Table 7) teach specific point mutations on SEQ ID NO: 1 (e.g., N266G) and the resulting VX and VR activity. However, the working examples of the specification do not teach multiple amino acid substitution in SEQ ID NO: 1, nor the resulting VX and/or VR activity. The specification provides minimal guidance on the modification of SEQ ID NO: 1. Page 99/Table 1 lists examples of conservative amino acid substitutions known in the art, but does not provide any evidence of these substitutions still possessing the same activity against VX and VR.
In summary, the specification does not teach that SEQ ID NO: 1 with no modifications can act as an OPNA hydrolyzing enzyme. The specification also does not teach how SEQ ID NO: 1 can comprise more than one of the claimed amino acid substitutions and still maintain the same function.
The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited functional language (i.e., IONA hydrolyzing activity, activity against VX and VR). The specification fails to disclose what structural changes to SEQ ID NO: 1 is/are necessary and sufficient to produce PTE/PTERs sharing the same functional properties (e.g., how many amino acid substitutions and what specific combinations would/would not result in the PTE/PTER having OPNA hydrolyzing activity and activity against VR and VX?), and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
The examiner notes that while SEQ ID NO: 1, representing a PTE or PTER derived from Mycobacterium sp. 852014-52450_SCH5900713 (Table 5, page 105 of the instant specification) is known in the art, there is no teaching or suggestion in the art of a PTE or PTER derived from Mycobacterium sp. 852014-52450_SCH5900713 acting as an OPNA hydrolyzing enzyme.
A search of the art for PTEs/PTERs derived from Mycobacterium sp. 852014-52450_SCH5900713 returned minimal results. While SEQ ID NO: 1 was previously known, the prior art did not teach the functional properties of PTEs/PTERs derived from Mycobacterium sp. 852014-52450_SCH5900713.
GenBank Accession OBF92671.1, published June 17th, 2016, is considered relevant prior art for teaching a PTE or PTER amino acid sequence derived from Mycobacterium sp. 852014-52450_SCH5900713, which shares 100% identity with instant SEQ ID NO: 1:
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University of Georgia (US 20160355792 A1, published 12/08/2016) is also considered relevant prior art for teaching genetically engineered organophosphorus acid anhydrolase polypeptides (OPAA), a class of phosphotriesterases, with broadened stereospecificity and increased activity for acetylcholinesterase-inhibiting organophosphorus compounds [0004, 0006]. The OPAAs taught by University of Georgia are engineered with increased catalytic efficiency for organophosphates, particular V-type nerve agents [0012]. University of Georgia teaches that OPAAs may be sourced from different species, such as Mycobacterium sp. [0058]. However, University of Georgia does not specifically mention Mycobacterium sp. 852014-52450_SCH5900713, or provide a specific reason for an artisan to use an OPAA from Mycobacterium sp. in general.
Given the lack of working examples in the specification of SEQ ID NO: 1 possessing OPNA hydrolyzing activity, and the minimal teachings in the art on the functional properties of Mycobacterium sp. 852014-52450_SCH5900713, the skilled artisan would conclude that Applicant did not possess SEQ ID NO: 1 as recited in claim 2 that retains biological activity as claimed.
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg. 63, col. 1), which in this case, would affect the ability of the genus of structurally undisclosed secretory protein variants so as to necessarily and predictably maintain the recited biological functional property(ies) of the corresponding protein.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg. 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg. 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg. 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg. 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered protein sequences of the claimed, but not structurally disclosed, genus of SEQ ID NO: 1 variants is considered to be notoriously difficult, slow, laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Given the large and structurally diverse genus of PTEs comprising a modified SEQ ID NO: 1, the lack of working examples in the specification of more than one amino acid substitutions in SEQ ID NO: 1, and in view of Ng et al., the skilled artisan would conclude that Applicant did not possess the genus of PTEs comprising a modified SEQ ID NO: 1 as recited in claim 15 that retain biological activity as claimed.
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.
Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 3, 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). It would be remedial to remove the recitation of “(such as VX or VR)”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 4, 10, and 11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Migal Galilee Research Institute (WO2020255131A1, published 12/24/2020; cited in PCT Written Opinion).
Regarding claims 1, 3, and 4, Migal discloses mutated phosphotriesterases and phosphotriesterase-like lactonases (i.e., a phosphotriesterase-related protein), including SEQ ID NOs: 99, 95, 104, 105, and 108, all of which share greater than 97% identity with instant SEQ ID NO: 1 (see pgs. 26-27). The mutated sequence may be present in a bacterial, fungal, mammal or plant cell (instant claim 4) (claim 26 of Migal).
While Migal is silent on the function of these PTEs and PTERs hydrolyzing OPNAs (e.g., V-agents- claim 3), Migal discloses all structures of the claimed host cell. As stated above, hydrolyzing OPNAs is considered a functional characteristic of the heterologous polynucleotide, and does not further limit the structure of the claimed host cell. There is nothing to suggest that the host cells disclosed by Migal would not also have the same OPNA hydrolyzing activity.
The claiming of an unknown property (e.g., hydrolyzing an OPNA/V-agent) which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
"In relying upon the theory of inherency, the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art." Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Inter. 1990) (emphasis in original).
Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evident or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference. MPEP §2112. "[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on 'inherency' under 35 U.S.C. 102, on 'prima facie obviousness' under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same...[footnote omitted]." The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977)).
Regarding claim 10, Migal discloses SEQ ID NOs: 99, 104, and 105, which share greater than 97% identity (but not 100%) with instant SEQ ID NO: 1. These sequences are also the exact same length as instant SEQ ID NO: 1 (see pgs. 26-27), Therefore, Migal discloses the PTE or PTER comprising one or more amino acid substitutions relative to the sequence of SEQ ID NO: 1.
Regarding claim 11, Migal discloses SEQ ID NOs: 99, 95, 104, 105, and 108, all of which share greater than 90% identity with instant SEQ ID NO: 149 (see pgs. 26-27).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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