DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response filed 12/04/2025 has been received and considered entered. This is a response to amendments and arguments filed 12/04/2025.
Claims Status
Claims 1, 3, 14 is/are cancelled. Claims 2, 4-13, 15-21 is/are currently pending. Claims 2, 4-13, 15-21 is/are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
112(a):
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 2, 4-11, 13-21 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. This rejection is updated in response to claim amendments and is maintained.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
Claims 2, 4-7, 9, 13, 15 recite amino acid sequences (claims 2, 5-7, 15) and nucleotide sequences (claims 4-5, 9, 13) “at least 90%” identical to enumerated sequences, encompassing any sequences at least 90% identical to those recited. The genera of species encompassing all sequences at least 90% identical to the recited amino acid and nucleotide sequences comprise enormous lists of possible sequence variants. Claims 14, 16-20 depend on claim 2, and claims 8, 10-11, and 21 depend on claim 7, but these claims do not further limit these possible variants as recited in the claims on which they depend.
The specification does not teach acceptable alterations or limitations on alterations to the recited amino acid or nucleotide sequences that would result in less than 100% sequence identity. Page 197 lines 17-19 discloses that amino acid sequences can be modified to create variations by introducing potentially unlimited mutations or variations, of any nature; page 23 lines 13-14 discloses that nucleic acid sequence mutations can comprise any number of mutations. No other discussion of acceptable modifications, variations, mutations, or alterations of amino acid or nucleotide sequences were found in the disclosure—including any discussion of sequence elements, structural components, or functional qualities that can be modified or eliminated, or which must be conserved as compared to the recited sequence which is modified. While the enumerated amino acid sequences are recombinases, and the nucleic acid sequences are recombinase recognition sequences, the language of the claims regarding sequence identity does not require that sequences with less than 100% sequence identity retain these functional or structural elements, nor that they retain the capacity to be classified as recombinases or recombinase recognition sequences, respectively, by a person of ordinary skill in the art. Thus, the genera of species created by the limitations of claims 2, 4-7, 13, and 15 are not limited by any sequence, structural, or functional constraints beyond mere sequence alignment. Additionally, the disclosure does not disclose a representative number of species encompassed by these genera which do not retain the functional and structural elements of the enumerated species (recombinase activity or sequence capable of being recognized by a recombinase).
According to the MPEP § 2163, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
In conclusion, Applicant’s disclosure of a limited number of species of each of the broad genera as described above, and lack of structural or functional limitations of these broad genera, is not deemed sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genera at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genera of claims 2, 4-11, 13, 15--21.
Response to Arguments
Applicant's arguments filed 12/04/2025 have been fully considered but they are not persuasive.
Applicant argues that “the instant specification provides extensive description of the sequences recited in the amended claims.” (page 15) The specification provides description of sequences 100% identical to SEQ ID NOs: 1-19, 21-626, 628-1214, 1215-1233, and 1235-1821. Applicant argues that “[a] person of ordinary skill in the art would reasonably expect that recombinase polypeptides and DNA recognition sequences comprising the amino acid sequences recited [in] the amended claims, or having at least 90% identity thereto, would share properties demonstrated in the Examples (e.g., capacity to modify DNA).” (page 15) While an artisan would be able to determine or assume specific modifications which a recombinase may be capable of tolerating while maintaining DNA-modifying functions in the case of recombinases whose structures are well-described in the art, the instant claimed recombinase species are not well described in the art and do not share significant sequence similarity to recombinases which are well described in the art. As neither the prior art nor the specification describe domains or structural elements which must be preserved or which may be modified of any of the claimed recombinase species, or describe any structure-function relationship of the claimed recombinase species, an artisan would not be able to determine which amino acid sequences at least 90% identical to, but less than 100% identical to, SEQ ID NOs:1215-1233 and 1235-1821 could function as recombinases and could recognize target sites of SEQ ID NOs: 1-19, 21-626, 628-1214. Furthermore, an artisan would not be able to determine that the applicants were in possession of a representative number of recombinase species or recombinase recognition sites less than 100% but at least 90% identical to SEQ ID NOs: 1-19, 21-626, 628-1214, 1215-1233, and 1235-1821.
Limitations not Found in Prior Art
Applicant has claimed 606 distinct amino acid sequences. Twelve recombinase sequences were searched by the Examiner (SEQ ID NOs:1218, 1234, 1241, 1243, 1244, 1274, 1350, 1450, 1550, 1660, 1740, 1821). Individual searching of all 606 distinct recombinase species is considered a search burden and cannot be performed. The twelve thorough sequence searches are considered the most thorough search feasible of the claimed breadth of sequences. No patent references were found which teach sequences at least 90% identical to these recombinase sequences. Sequences 90-100% identical to these sequences were found in the UniProt database, corresponding to putative recombinase sequences derived from whole genome sequencing of different bacterial species, including multiple Pantoea species. However, none of the sequences found in the UniProt database were described in the art, including corresponding target sequences, whereas the pending claims require corresponding recognition sequences (SEQ ID NOs:1-19, 21-626, 628-1214). Furthermore, these amino acid sequences did not have significant sequence identity to Cre and Cre-like recombinases known in the art (such as Panto, VCre, Dre; see Karimova, 2016, of record), whose target sequences have been described. Surendranath (2010; of record) teaches a computer tool for identification of novel or degenerate recombinase recognition sites, but requires knowledge of a recombinase protein’s target recognition site, and as such would not be obvious to an artisan as applicable to recombinases whose target recognition sites have not been described. As such, while the protein sequences were known or assumed to be tyrosine recombinases prior to the time of filing, an artisan would not be able to determine, based solely on the protein sequences, the target sequences required for recombination.
Claim 12 is allowed.
The following is a statement of reasons for the indication of allowable subject matter: A search of the art for human safe harbor sites produced multiple references, including Pellenz (2018). However, a comparison of the safe harbor sites taught by Pellenz and the sequences of SEQ ID NOs:1-19, 21-626, 628-1214 (whose corresponding loci in the human genome are taught in the specification and searched in BLAST) shows that the claimed sequences are separated from known safe harbor loci in the same chromosomes by tens or hundreds of thousands of nucleotides. The specification recites genomic locations which consist of SEQ ID NOs: 1-19, 21-626, 628-1214—comprising no more than SEQ ID NOs: 1-19, 21-626, 628-1214—and thus “having” in claim 12 is interpreted in light of the specification to mean “consisting of” (see MPEP §2111.03(IV)). These human safe harbor loci are taught by the instant specification to be targeted by recombinase proteins which are not naturally found in humans or in human pathogens (based on BLAST and UniProt searches for a representative number of recombinase sequences). An artisan would need to search through eukaryotic genome sequences for novel safe harbor sites in order to find SEQ ID NOs: 1-19, 21-626, 628-1214. Thus, a eukaryotic cell comprising in its genome one of SEQ ID NOs:1-19, 21-626, 628-1214 and a heterologous sequence inserted into the genomic sequence of SEQ ID NOs: 1-19, 21-626, 628-1214 would neither be naturally occurring nor obvious to create.
Conclusion
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.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636