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 .
This Official Action was necessitated following the Pre-Appeal brief filed 13 January 2026 and subsequent decision to reopen. See Pre-Appeal Conference decision posted 09 February 2026.
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, 21-77, 83, and 85-86 were previously cancelled, claims 20, 74-82, 84, 87-91 have been considered on their merits.
Withdrawn Rejections
Applicant’s arguments, see pre-appeal brief, filed 13 January 2026, with respect to the rejection under 35 USC 103 have been fully considered and are persuasive. The rejection under 35 USC 103 has been withdrawn.
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, 74-82, 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 a new interpretation of the claims.
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.
Independent claim 20 encompasses a genus of any two vectors comprising any vector, any gene of interest, any first recombination site, any second recombination site, and any site-specific recombinase. Additionally, considering the implied utility of a vector comprising a functional gene of interest, these elements are broad to encompass components which are not required to be compatible. The claim does not limit the relative position of the required components, as such, the recombination sites could be positioned in an intronic or exonic region. Since the recombination site sequence can be left behind depending on positioning following transcription and translation, which would result in this “scar” sequence being present in the gene product and lead to a dysfunctional gene of interest. Further, this claim is presented in a manner which does not require the recombinase to be expressed. Considering the lack of structure-function relationship, the claim is broad to encompass a composition with no utility and does not require the components of the vectors to work together which could result in a dysfunctional gene of interest.
Claim 74 encompasses the first vector further comprises any promoter and any splice donor site, however, the claim does not limit the position of these components and does not require the presence of a splice acceptor site.
Claim 75 encompasses the first vector further comprises a 5’ ITR and a 3’ ITR.
Claim 76 encompasses the second vector further comprises any splice acceptor, however, the claim does not limit the position of the splice acceptor and does not require the presence of a splice donor site.
Claim 77 encompasses the second vector further comprises a 5’ ITR, a 3’ ITR, and a poly-A site.
Claim 78 encompasses the nucleic acid encoding the genus of site-specific recombinases is operably linked to any promoter.
Claim 79 encompasses the genus of recombinases, a Cre recombinase.
Claim 80 encompasses the species of the first recombination site, loxP.
Claim 81 encompasses the species of the second 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.
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 did not demonstrate possession of the full genus of vectors, genes of interest, recombination sites, or site-specific recombinases.
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.
Actual Reduction to Practice & Disclosure of Structure
Applicant demonstrated the claimed two-vector design, Fig. 1A, wherein the assembly of two AAV viral payloads 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.
Applicant, at the top of p. 7, describes the vector is 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. 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, to include the orientation of the vector elements. 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 Examiner concludes that there is insufficient written description of the instantly claimed genus of vectors and vector components. Specifically, there is limited description of the structure-function relationship between the positioning and/or presence of splice acceptors, splice donors, and promoters. Additionally, the claimed genus of recombination sites and recombinases and their ability to predictably form a functional gene of interest. Therefore, the Examiner concludes the skilled artisan would find the specification inadequately describes the claimed genus of vectors and vector components.
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 20, 74-82, and 87-88 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.
This is a new rejection, necessitated by a new interpretation of the claims.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: a splice acceptor site, a splice donor site, and a promoter. These elements would be required for the composition to form a functional gene of interest. In the instant composition, the patentable features which distinguish the composition from the prior art are the structure of the vectors themselves. However, absent claim language indicating the structure of the vectors, a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement. Dependent claims 74-82, and 87-88 are included in the basis of the rejection because although they recite and encompass the composition of claim 20, they do not clarify the structure of the vectors. As an example, while claim 74 depends from claim 20 and requires the splice donor site, it does not require the splice acceptor site. Similarly, claim 76 depends from claim 20 and requires the splice acceptor site, it does not require the splice donor site.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are: The claim omits the essential structure between the recombinase and the recombination sites. The functional relationship between these elements is limited to a set of related sets which are known to function and interact with one another. The claim, as written, does not require the recombination sites to be that of the same set nor the recombinase to be part of the same recombination system. In the instant composition, the patentable features which distinguish the composition from the prior art are the relationship of the recombinase and recombination sites. However, absent claim language indicating the relationship of the recombinase and recombination sites, a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement. Dependent claims 74-82, and 87-88 are included in the basis of the rejection because although they recite and encompass the composition of claim 20, they do not clarify the structure of the vectors. As an example, claim 79 depends from claim 20 and requires the recombinase, Cre, yet does not require the recombination site which is part of the same recombination system. Similarly, claim 80 depends from claim 20 and only requires the first recombination site, loxP, yet does not require the corresponding recombinase nor the second recombination site.
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.
Applicant’s arguments, see Pre-Appeal Brief, filed 13 January 2026, with respect to the rejections under 35 USC 103 have been fully considered and are persuasive. The rejections of 01 October 2025 have been withdrawn.
Conclusion
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.
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/N.A.H./Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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