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 .
Election/Restrictions
The initial election was made without traverse in the reply filed on 02/04/2025. Applicant cancelled all non-elected claims.
Claim Status
Claims 1-19, 21-73, 83, and 85-86 were previously cancelled, claims 74, 76, 78, 81 are newly canceled, claims 20, 75, 77, 79-80, and 90 are currently amended, and claims 20, 75, 77, 79-80, 82, 84, and 87-91 have been considered on their merits.
Withdrawn Rejections
The rejection under 35 U.S.C. § 112(a) has been withdrawn due to Applicant’s amendments to the claims. However, upon further consideration a new rejection is set forth below.
The rejection under 35 U.S.C. § 112(b) has been withdrawn due to Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112
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 20, 75, 77, 79-80, 82, 84, and 87-88 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.
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the rejection below.
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.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination. Applicant did not adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of compositions.
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. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
Independent claim 20 encompasses a genus of any two vectors comprising any vector system, any two segments of a gene of interest, any two recombination sites which are capable of catalyzing site-specific recombination to produce said gene of interest, and any site-specific recombinase.
Claim 75 encompasses the first vector further comprises a 5’ ITR and a 3’ ITR.
Claim 77 encompasses the second vector further comprises a 5’ ITR, a 3’ ITR, and a poly-A site.
Claim 79 encompasses the genus of recombinases, a Cre recombinase.
Claim 80 encompasses the species of the first recombination site, loxP.
Claim 82 encompasses the species of gene of interest, ABCA4.
Claim 84 encompasses the broad genus of the gene of interest, to include any therapeutic protein. A segment of any gene of interest could include non-coding regions and regulatory elements, not just coding regions. The language of the claim could also include segments of a gene which would exceed the size capacity of any vector. For example, if said first and second vector were AAV, a therapeutic gene of interest which requires larger than ~9-10 kb in total payload will exceed the capacity of a dual AAV system, including large structural genes, multi‑exon coding sequences, and complex multi‑component systems. Therefore, the language of the claim exceeds the breadth of the claim limitation.
Claim 87 encompasses the genus of the first vector, any AAV vector, however, does not limit the species of the second vector.
Claim 88 encompasses the genus of the second vector, any AAV vector.
Accordingly, Applicant’s disclosure does not demonstrate possession of the full genus of vectors, genes of interest, recombination sites, or site-specific recombinases which would result the production of a functional gene of interest.
Actual Reduction to Practice & Disclosure of Structure
Applicant displays the structure of the claimed two-vector design, Fig. 1A, wherein the assembly of two AAV viral payloads comprising a first and second exon of a gene of interest using site-specific recombinases (SSR). (1) AAV viral vectors showing placement of recombination sites (RS). 2-vector system has bxbl contained on one of the same virus as assembled cargo. (2) SSR catalyzes ligation of vectors together. (3) Transcription and RNA-splicing yields gene product (Fig. 1A description, p. 8). The figure includes all of the required components and relative positions; to include the ITRs, promoters, splice acceptor and donor sites to reasonably convey a functional gene of interest. Additionally, it is noted that this figure exemplifies the bxb1 site-specific recombination system, not the Cre/lox system as claimed in claims 79 and 80.
In example 3, found on page 18 of the instant specification, results from the two AAV2 vectors by Bxb1 integrase using a 2-vector design strategy are discussed. The results indicated successful assembly of mKate fluorescent protein gene in living mammalian cells, wherein wild type Bxb1 displayed 5.42% gene expression, as seen in Fig. 3. However, with a 5.42% expression rate compared to the 99.4% expression rate of the control, there is no indication that these results are significant as no statistical analysis is present.
Applicant describes an example of a dual plasmid system, Fig. 5A/Example 5. However, this figure is not commensurate in scope with the claims as the recombinase, Cre, is provided separate from the two plasmids. Although, Fig. 5B and 5C display how this system utilizing lox recombination sites does not work with any recombinase, only with Cre, as applying Flp was ineffective at expressing the gene of interest.
Applicant, at the top of p. 7, describes the vector as a plasmid or a viral vector, wherein the viral vector is selected from the group consisting of adeno-associated viral vectors, adenoviral vectors, lentiviral vectors, and retroviral vectors. At p. 9, lines 14-21, Applicant describes the detailed description of “Vectors”, a vector used as provided herein, in some embodiments, is a viral vector. Applicant does not discuss the use of other vectors besides that of AAV, thus, not showing possession of the claimed genus of any vector.
Applicant describes fourteen suitable therapeutic genes/proteins on p. 12 in Table 1: USH2A, PKD1, ALMS1, PKHD1, VPS13B, DMD, HD, COL7A1, CEP290, ABCA4, MYO7A, NHS, COL17A1, and CFTR. This list of therapeutic genes/proteins does not encompass the full genus of any gene of interest as claimed in independent claim 20.
However, Applicant’s specification has not provided guidance nor descriptions of the claimed genus of components required for the claimed two-vector system which would be capable of forming a functional gene of interest. The gene of interest is described in claim 20 as a first and second segment, which does not necessarily mean these segments comprise exons. The language of the claim is broad to include introns or other noncoding sequences. Therefore, the skilled artisan would not know what rational approach to take to make the genus of compositions with any predictable outcome on function. Thus, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of compositions to include the genus of any first and second vector, any gene of interest, any first and second recombination site, and any recombinase.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
State of the Art & Quantity of Experimentation
The state of the art describes the structure-function relationship required between recombinase and recombination sites.
Ow et al. (US2011/0136237, IDS ref., of record) teach site-specific recombination permits the precise deletion, inversion, integration, or translocation of DNA sequences (para. [0006]). Ow teaches numerous site-specific recombination systems have been described in prokaryotic and lower eukaryotic organisms wherein each recombination system consists of a recombinase enzyme and a set of recombination sites (para. [0011]). Ow teaches the application of bacterial recombinase systems, Cre-lox, for site-specific excision, inversion, co-integration, or translocation for the precise genetic modification of eukaryotic genomes (para. [0003] and [0015]). Ow teaches nucleic acids including recombination sites, as well as nucleic acids in which a recombinase-encoding polynucleotide sequence is operably linked to a promoter which functions in the target eukaryotic cell (para. [0160], Constructs for Introduction of Exogenous DNA into Target Cells). Ow teaches site-specific recombination in mammalian cells, wherein one assay relied on the site-specific recombination between recombination sites situated on two separate DNA molecules (para. [0234]). The teachings of Ow demonstrate what is required of site-specific recombination to predictably function, to include a recombination system consisting of a recombinase and a set of recombination sites, wherein a promoter operably linked to the recombinase for proper function. It would be unpredictable to expect the recombinase to function without the appropriate set of recombination sites and the corresponding recombinase operably linked to a promoter.
Reece-Hoyes et al. (Cold Spring Harb Protoc; 2018(1), of record) teach the Gateway recombinatorial cloning system for cloning multiple DNA fragments in parallel in a standard manner using the same enzymes (Abstract). Reece-Hoyes teaches the sites of recombination (“att” sites) are much longer (25–242 bp) than restriction sites, they are extremely unlikely to occur by chance in DNA fragments (Abstract). Reece-Hoyes teaches Gateway cloning is based on the highly specific integration and excision reactions of bacteriophage λ into and out of the Escherichia coli genome (p. 2, 1st para.). Reece-Hoyes teaches the Gateway cloning system uses two different enzyme mixtures, each of which performs a different type of recombination reaction. Reece-Hoyes teaches the BP clonase enzyme mix recombines attB sites with attP sites generating attL and attR sites (p. 2, 1st para.). Reece-Hoyes teaches each recombination event is precise, with no nucleotides either gained or lost (p. 2, 1st para.). Reece-Hoyes teaches introducing nucleotide changes within the 25-bp recognition region (Fig. 1C) has been used to engineer different subtypes of att sites that recombine only with each other (i.e., attB1 sites with attP1 sites, but not with attP2 or attP3 sites) (p. 2, 1st para.). Reece-Hoyes teaches these different sets of att sites facilitate cloning of each DNA fragment in only one orientation (Fig. 2) into each vector (e.g., by placing a different attB site at either end) (p. 2, 1st para.).
The Gateway cloning method of Reece-Hoyes is one of a finite number of recombination methods known to be capable of precise recombination or insertion of genes in an attempt to provide optimized recombination of a full-length protein. Additionally, Reece-Hoyes teaches recognition of att sites is extremely specific (i.e., BP clonase enzymes never use attL or attR sites), thus every recombination reaction generates only one set of derivatives (p. 2, 1st para.). Reece-Hoyes demonstrates the specific orientation and relationship required for these recombination systems to function as expected. It would be unpredictable to expect any recombination site to function properly in any orientation or without its specific set of corresponding recombination sites.
Thus, the state of the prior art established the structure function relationship between recombination sites and recombinases. It would be unpredictable to expect unrelated species of recombination sites and recombinases to function in a manner providing a functional product. Further, one of ordinary skill in the art would neither expect nor predict a functional relationship between unrelated species or a functional gene of interest according to the claimed genus of compositions.
Conclusion
Therefore, the instant disclosure has not resolved the long-standing unpredictability found in the prior art based on the limited showing of actual reduction to practice which utilizes the claimed 2 vector design. Furthermore, the Examiner concludes that the skilled artisan would find the specification inadequately describes the claimed genus of vectors, genes of interest, recombination sites, and site-specific recombinases.
Response to Traversal
Applicant's arguments filed 17 September 2026 have been fully considered but they are not persuasive.
While Applicant’s amendments to the claims further define the structure of the claimed composition, the claim still recites a scope which is not commensurate with the disclosed contribution to the art. Since the prior art is limited regarding the claimed two vector design composition, it is up to Applicant to exemplify their contribution to the art by providing evidence of what has been reduced to practice.
In response to Applicant's argument regarding the specification disclosing a representative number of species of vectors, genes of interest, recombination sites, and recombinases; while this may be the case, the species are not recited in the rejected claims. Due to the limited showing and the level of unpredictability in the art, objective evidence beyond what has already been discussed would be required to overcome the present rejection. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Broad disclosures of the specification and prophetic examples do not satisfy the written description requirement when the art is unpredictable. Applicant is required to specifically define their contribution when the art does not support the breadth of the claim. Amending the claims to represent what has been reduced to practice would be sufficient to overcome the present 112(a) rejection.
Allowable Subject Matter
Claims 89-91 are allowed.
The following is a statement of reasons for the indication of allowable subject matter: The subject matter of claim 89 is free of the prior art as indicated in the Official Action mailed 17 June 2026. Claims 90 and 91 depend from claim 89, therefore, also comprise allowable subject matter.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NICHOLAS A. HUMPHRIES whose telephone number is (703)756-5556. The examiner can normally be reached Monday - Friday, 7:30am - 4:30 pm.
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, James Schultz can be reached at 571-272-0763. 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.
/N.A.H./Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
Prosecution Insights