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 1-6 and 15-18, 21-25, and 27-31 are pending.
Claims 1-6 are withdrawn.
Claims 15-18, 21-25, and 27-31 are under examination.
New Objections to Drawings
The Drawings are objected to because they does not conform to sequence rules, requiring the use of “SEQ ID NO:” (37 CFR 1.821-1.825).
Figure 16C contains sequences which are not labeled with a corresponding sequence identifier (unlabeled sequences copied below).
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Where the description or claims of a patent application discuss a sequence that is set forth in the “Sequence Listing” in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by “SEQ ID NO:” in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. 37 CFR 1.821 (d).
The applicant is reminded that claims and specification must be amended in order to comply with regulations cited above. All references to sequences in claims and specification should be referred to as “SEQ ID NO:1”, for example. To avoid all doubts of the examiner and to ensure correct interpretation of the claims and specification, the identification of sequences with proper sequence identifiers is required.
Withdrawn New Claim Rejections - 35 USC § 112(a)
New Matter
The rejection of claim 26 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), first paragraph, as failing to comply with the written description requirement due to the presence of new matter is withdrawn in view of the cancellation of this claim.
The rejection of claim 28 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), first paragraph, as failing to comply with the written description requirement due to the presence of new matter is withdrawn in view of Applicant’s arguments.
Withdrawn Claim Rejections - 35 USC § 112(a)
Written Description
The rejection of claims 15-18, 21-25, and 27-29
The rejection of claims 19-20 and 26 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paragraph, as failing to comply with the written description requirement as set forth in the previous office action is withdrawn in view of the cancellation of these claims.
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 15-18, 21-25, and 27-31 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.
The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). 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 2163.04.
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 a disclosure of a representative number of species to describe the complete structure of the claimed genus and/or disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
Scope of the Invention
In the instant case, the genus is guide molecules “to direct the Cas nuclease to a 5' UTR of an endogenous nucleic acid encoding the mutated RHO gene variant” as part of a method in human subject.
The broadest reasonable interpretation of the scope of this genus encompasses all possible guide molecules targeting all possible regions of the human RHO gene 5’UTR. Because a specific Cas is not claimed, this encompasses guide molecules targeting all possible regions that include all possible PAM sequences for all possible Cas types and mutants on either strand of the 5’UTR.
Disclosure of Structure and Disclosure of Species
Regarding guide molecules targeting all possible regions of the human RHO gene 5’UTR, Applicant does not disclose a specific species of a specific sequence of a guide molecules targeting the human RHO gene 5’UTR.
It Is noted that Applicant discloses guide RNAs targeting SEQ ID NO:20 or 21(see Figure 2; Example 1-2) which target the mouse RHO gene 5’UTR and are materially distinct embodiments of guide molecules.
It is noted that Applicant discloses 4 guide RNAs of SEQ ID NO: 4-7 (table on pg. 100), which appear to target mouse RHO ATG upstream and are materially distinct embodiments of guide molecules.
Structure/Function Correlation
Regarding the guide molecules, as stated above, Applicant discloses 6 gRNAs that target materially distinct mouse sequences, while Applicant does not disclose species of a specific guide molecule that targets the human RHO 5’UTR.
Although human and mouse sequences share homology, a mouse guide RNA will not function on a human sequence, and therefore a materially different design, which is a materially different guide RNA sequence, is required to target human genes with guide molecules. Applicant’s disclosed mouse sequences (SEQ ID NO: 4-7 and SEQ ID NO:20-21) do not align with the human genome (see attached UCSC BLAT alignment) and would therefore not function in the human genome, and are materially distinct guide RNA sequences are required to target to human RHO 5’UTR, and cannot provide support for a genus of guide molecules that target human sequences. Because the disclosed guide sequences do not align to the human genomes, they cannot be considered correlates to target the human RHO 5’UTR.
Regarding the structure function relationship of guide molecule design, Applicant is directed to the art of Corsi et al. (Nat Commun. 2022 May 30;13(1):3006.; henceforth “Corsi”). Corsi evidences that the structure/function relationship of guide RNAs is not predictable. Specifically, Corsi evidences that in the art, a large number of in silico methods for gRNA design report that the cleavage efficiency of Cas9 can largely vary due to the sequence and structural properties of the gRNA (pg. 2 col. 1 2nd para.). Corsi evidences that not all guide RNAs cleave DNA efficiently, gRNAs display changes in efficiency at on- and off-target sites, and gRNAs can even cleave an off-target with higher efficiency than the intended on-target site (abstract; pg. 1). Corsi further evidences recent studies report that the mismatch tolerance patterns of different gRNAs can highly variate (pg. 10 col. 2).
Regarding the structure function relationship of guide molecule design, Applicant is additionally directed to the art of Mohr et al. (FEBS J. 2016 Sep;283(17):3232-8. Epub 2016 Jun 22.; henceforth “Mohr”). Mohr evidences guide RNA design for the particular Cas9 application, and for the same application in different species requires different rules for gRNA effectiveness (pg. 3233 col. 2 2nd para.). Mohr evidences even groups working in the same species have identified different criteria associated with effectiveness and reports of improvements relevant to one species await further validation in the same and other systems (pg. 3233 col. 2 2nd para.).
Regarding the structure function relationship of guide molecule design, instant claims require integration by HITI. As stated above, the specific application of CRISPR requires specific gRNA design, as evidenced by Mohr, and this design needs to be further validated because Mohr evidences the same Application in different species requires different rules for gRNA effectiveness. Applicant is directed to the art of Tornabene et al. (Nat Commun. 2022 Apr 12;13(1):1963.; see IDS filed 22nd, May, 2025; henceforth “Tornabene”). Tornabene evidences that shortly before around the time of filing, specific gRNA design is required for HITI methods (“inverting its gRNA target sequences” pg. 2 col. 2 1st para.). Tornabene evidences HITI precision and off-target integration need to be further characterized (pg. 2 col. 2 1st para.).
In sum, the collective evidence of the art at or around the time of filing is that specific gRNA design is required for specific Cas application, as evidenced by the art of Mohr, the same application in different species may require different design rules for gRNA effectiveness, as evidenced by Mohr, and the required mechanism of HITI of instant claims is not a fully characterized application of Cas at or around the time of filing, as evidenced by Tornabene. In other words, because the Cas application of HITI is not well characterized, and because Cas Applications requires specific gRNA design characteristics that may not be consistent between different species, one of ordinary skill could not envision the requisite structural elements of the gRNA which targets the 5’UTR of the human RHO gene specifically for HITI applications at the time of filing.
Applicants disclosure of mouse gRNA sequences does not provide a nexus between the required gRNA structures and their required function as part of a HITI method because Mohr evidences the different species requires different rules for gRNA effectiveness. Further, for the reasons stated above, the state of the art does not remedy this deficiency and further evidences that the structure/function relationship between gRNAs and HITI methods cannot be predictably envisioned by one of ordinary skill in the art.
Written Description Conclusion
Therefore, the examiner concludes there is insufficient written description support for the instantly claimed genera. Specifically, there is no description of specific gRNAs that target the 5’UTR of the human RHO gene. The specification merely describes 6 species of mouse gRNAs that do not correlate with the human gRNAs for the reasons stated above (see “Structure/Function Relationship” above). The specification does not disclose any specific species of human gRNA sequences that target the 5’UTR of the human RHO gene. The massive genes of human gRNAs encompassed by instant claims are not supported by the disclosure of mouse sequences. The instant specification has failed to provide any species examples of guide molecules targeting the human RHO gene 5’UTR to represent the vast number of structurally and functionally diverse species of guide molecules. Further, the specification fails to provide a nexus between the structure of the claimed guide molecules and their required function as part of a HITI method. This nexus is not remedied by the state of the art. Thus, in the face of an unpredictable art, one of ordinary skill in the art could not envision the requisite structural elements and the elements that could be modified from the disclosures of the application or art at the time of filing.
Response to Arguments
Applicant’s amendments to human subjects necessitated the new grounds of rejection above. For the sake of compact prosecution, arguments considered pertinent to the new grounds of rejection are addressed below.
Applicant’s arguments, filed 5th, August, 2025, have been fully considered but are not found persuasive.
Applicant argues “the art is such that Applicant's adRP mouse model is recognized as correlating to adRP and should be accepted as supporting and enabling Applicant's in vivo method of treating.
M.P.E.P. § 2164.02(11)” (pg. 8-9; also pg. 10 last para.).
In response, although Applicant’s mouse model is an art recognized model of the symptoms and disease of adRP, it does not remedy the issues of Written Description above because the state of the art indicates that guide RNA design is not predicably translatable from mouse to humans and therefore one of ordinary skill could not envision the required structural elements of the guide molecule of instant claims from the disclosure of only mouse guide RNAs
Withdrawn Claim Rejections - 35 USC § 112(a)
Scope of Enablement
The rejection of claims 19-20 and 26 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph because the full scope of the claims was not enabled is withdrawn in view of the cancellation of these claims.
The rejection of claims 15-18, 21-25, and 27-29 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph because the full scope of the claims was not enabled is withdrawn in view of Applicant’s amendments.
New Claim Rejections - 35 USC § 112(a)
Enablement
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 15-18, 21-25, and 27-31 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Wands Factors
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
Breadth of the Claims
Instant claims encompass:
Methods for treating autosomal dominant retinitis pigmentosa
“in a human subject identified as expressing a mutated RHO gene variant”
This includes all possible human subject types that have all possible mutated RHO gene variants in all possible locations of the RHO gene.
Comprising
“transducing”
This includes all methods of transducing including all possible methods of introduction such as injection, electroporation, topical administration, or others.
Further, this includes transduction at any time point of the disease or any time point before disease progression.
“a guide molecule to direct the Cas nuclease to a 5' UTR of an endogenous nucleic acid encoding the mutated RHO gene variant”
This includes all possible guide molecules to all possible target locations of the 5’UTR of the subject.
“wherein expression of the wild-type RHO gene treats autosomal dominant retinitis
pigmentosa in the subject”
This includes treatment of all types including symptom alleviation or amelioration of any amount for all possible symptoms of retinitis pigmentosa.
Direction or Guidance Presented
While contemplating human subjects, the specification provides limited guidance on methods in human subjects.
While contemplating guide molecules directed to the 5’UTR, the specification provides limited guidance on a specific target region of the 5’UTR for specifically a mouse model (Examples 1-2).
While contemplating embodiments of treating, the specification provides limited guidance on the symptoms of retinitis pigmentosa to be treated (para. [0003-0004, 0010, 0027, 0037, 0044-0045, 0049, 0055, 0059, 0060-0061, 0089-0090, 0093-0096, 0101-0102, 0110-0111, 0205-0206, 0211, 0220, 0229-0231, 0234, 0237, 0242, 0244, 0269]).
Present Working Examples
Examples 1-2
Example 1 is directed to a mutation-independent strategy to treat rhodopsin (RHO) associated autosomal dominant retinitis pigmentosa (adRP) in a mouse model.
Example 2 describes the experimental methods associated with Example 1.
Mouse Model of adRP
Autosomal disorder
autosomal dominant retinitis pigmentosa (adRP)
Mutated gene variant:
RHO P23H/wt mice were used.
Wildtype gene inserted:
Wildtype Rhodopsin
Method of introducing to the cell in the subject:
Crispr System with specifically SEQ ID NO: 20 gRNA (SEQ ID NO: 21 was also tested), SpCas9, and an hRK promoter. Dual AAV vectors (figure 7) were administered by subretinal injection at postnatal day 1 (P1) to one eye with the second eye as an internal control. Specifically, the vectors pAAV-hRK-SpCas9 (SEQ ID NO:31), pAAV-hRK-mCherry-U6-gRNA 1 (SEQ ID NO:32), pAAV-hRK-mCherry-U6-gRNA I -RHO- HITI donor (SEQ ID NO:33), and pAAV-hRK-mCherry-U6-gRNAI-GFP-HITI donor (SEQ ID NO:34) were used (Example 2).
Symptoms treated:
Photoreceptor thickness was increased from P60 to P210 in the RHO KI group in comparison to the control groups (FIGS. 8-9).
At late stages, photoreceptor thickness appears to be better preserved in RHO KI treatment (At the endpoint of the experiment, histological analysis of the harvested eyes showed that RHOKI treatment better preserved photoreceptor cell layer thickness with more Rhodopsin+ rods and better cone morphology (FIGS. 11-13)).
Rod light-sensing function appears to be improved at from P180 to P210 (RHO KI eyes have significantly higher scotopic ERG B- wave amplitude under dim light condition; Figures 8-11).
At late stages, both rod and cone function appear to be improved at scotopic light levels (Both rod-cone mixed scotopic ERG and cone-dominant photopic ERG showed increased amplitude with RHOKI at late stages (FIG. 10, FIG. 21)).
Absent Working Examples
No working examples are provided in a human subject.
No working examples are provided with human guide RNA molecules.
No working examples or proof-of concept examples are provided in human cells or tissues.
State of the Art and Unpredictability of the Art
The state of the art is unpredictable. One of ordinary skill would neither expect or predict the appropriate functional results of treating autosomal retinitis pigmentosa in a human subject with the instantly claimed method.
Photoreceptor Types
Instant claims are drawn to transducing photoreceptor cells of a subject with a wild-type RHO gene. However, photoreceptors include cone photoreceptors which do not express rhodopsin and instead express cone opsins. Therefore, instant claims are not enabled for expression of rhodopsin in all photoreceptor types because correction of the RHO gene in cone photoreceptors would have no effect on the pathology of retinitis pigmentosa.
Translating Mouse Methods to Humans
Applicant’s claim encompasses a method of gene therapy using CRISPR-Cas components in human subjects while Applicant’s examples utilize a mouse model of autosomal dominant retinitis pigmentosa.
Generally speaking, it is well known in the art the translation of findings from a mouse to human subject is not trivial. This general concept is evidenced by, for example, Larkindale (2011, accessed at: https://www.mda.org/quest/article/why-does-it-take-so-long-go-mouse-man#:~:text=Furthermore%2C%20curing%20a%20mouse%20is,mouse%20but%20not%20in%20patients.). Larkindale states “curing a mouse is not the same thing as curing a person. Animal models of a disease are just that — models” (pg. 2 4th para.). Although Larkindale is not drawn to CRSIPR-Cas methods or mouse models of adRP, the art of Larkindale generally evidences the well-known concept in the art that treatments that work in mice may not work in humans. In other words, treatments that work in mice are not predictably translatable to humans.
Translating Mouse Methods to Humans
CRISPR-Cas Methods
Regarding the instantly claimed method specifically, although the adRP model used by Applicant is cited as an art recognized model (“Applicant's adRP mouse model provided by Jackson Laboratory "mimics the retinopathy and progressive retinal degeneration observed in patients with autosomal dominant retinitis pigmentosa” Arguments filed 5th, August, 2025), the issue of the lack of translatability of CRISPR-Cas methods from mouse to humans remains and is addressed below. In other words, because CRISPR-Cas methods do not predictably translate from mouse to humans, although the adRP mimics the retinopathy and progressive retinal degeneration observed in patients with autosomal dominant retinitis pigmentosa, it can’t be assumed that the claimed method would be operable in humans because CRISPR-Cas methods do not predictably correlate from mice to humans for the reasons stated below.
Applicant is first directed to the art of record of Dai et al. (Mol Ther Nucleic Acids. 2016;5(8):e349.; henceforth “Dai”), Dai evidences CRISPR-Cas systems for gene editing are unpredictable. Specifically, Dai evidences one of the major hurdles to the clinical translation of CRISPR-Cas9 is its off-target effects, which may lead to uncontrollable and unpredictable consequences including malignant transformation (pg. 2 col. 2 3rd para.). Dai further evidences that due to the potential devastating nature of off-target effects, they must be studied thoroughly and tested in large-animal models before applied to humans (pg. 2 col. 2 4th para.). Dai further evidences Possible host immune responses triggered by Cas9 proteins or delivery vehicles represent another layer of hurdles to the in vivo therapeutic applications of CRISPR-Cas9 (pg. 3 1st col. last para.). Dai evidences Immunogenicity of viral vectors is a common problem encountered in gene therapy endeavors and Cas9 proteins or peptides are also of potentially immunogenicity given their bacterium origin (pg. 3 1st col. last para.).
Applicant is next directed to the art of Uddin et al. (Front Oncol. 2020 Aug 7;10:1387.; henceforth “Uddin”). Uddin evidences issues of predictability with CRISPR-Cas systems in humans. Specifically, Uddin evidences off-target effects of CRISPR systems (pg. 3-6 LIMITATIONS AND ADVANCEMENTS OF CRISPR/Cas9 “Off-Target Effects”). Uddin evidences CRISPR-induced DSBs can trigger apoptosis rather than the intended gene edit (pg. 6 col. 2 “DNA-Damage Toxicity”). Uddin further evidences toxicity as an issue, with an art example that more than half of human subjects in a study possessed preexisting anti-Cas9 antibodies against the most commonly used bacterial orthologs, SaCas9 and SpCas9 (pg. 7 col. 1 1st para.).
Applicant is finally directed to Applicant’s own arguments which state “it is well known that gene editing is not precise, but causes many genetic errors, with unpredictable results, in addition to any intended genetic change” (pg. 12-13).
Therefore, because Applicant’s arguments evidence that gene editing is known in the art to be unpredictable, Applicants specification, which evidences treatment in a mouse model when specifically administered specifically at P1, which is before the retinal circuit is considered complete at P21, cannot enable a method of treatment in humans across all time points of disease progression.
Guide Molecule (gRNA) Design for Mice versus Humans
Further regarding CRISPR-Cas methods, regarding guide RNA design, Applicant is directed to the art of Corsi et al. (Nat Commun. 2022 May 30;13(1):3006.; henceforth “Corsi”). Corsi evidences guide RNA design is not predictable. Specifically, Corsi evidences a large number of in silico methods for gRNA design report that the cleavage efficiency of Cas9 can largely vary due to the sequence and structural properties of the gRNA (pg. 2 col. 1 2nd para.). Corsi evidences that not all guide RNAs cleave DNA efficiently, gRNAs display changes in efficiency at on- and off-target sites, and gRNAs can even cleave an off-target with higher efficiency than the intended on-target site (abstract; pg. 1).
Applicant is next directed to the art of Mohr et al. (FEBS J. 2016 Sep;283(17):3232-8. Epub 2016 Jun 22.; henceforth “Mohr”). Mohr evidences the particular Cas9 application, and for the same application in different species requires different rules for gRNA effectiveness (pg. 3233 col. 2 2nd para.). Mohr evidences even groups working in the same species have identified different criteria associated with effectiveness and reports of improvements relevant to one species await further validation in the same and other systems (pg. 3233 col. 2 2nd para.).
Applicant is finally directed to the art of Tornabene et al. (Nat Commun. 2022 Apr 12;13(1):1963.; see IDS filed 22nd, May, 2025; henceforth “Tornabene”). Tornabene evidences that shortly before around the time of filing, specific gRNA design is required for HITI methods (“inverting its gRNA target sequences” pg. 2 col. 2 1st para.). Tornabene evidences HITI precision and off-target integration need to be further characterized (pg. 2 col. 2 1st para.).
In sum, the state of the art evidences that gRNA design is not predictable because, as evidenced by Mohr, the design considerations for the same application in different species are different and require further validation, and as evidenced by Tornabene, HITI-based CRISPR methods, which require specific gRNA design, also need to be further characterized.
Therefore, instant claims, which specifically require a guide molecule that targets a human 5’UTR of the RHO gene for a HITI-based method are not enabled by the instant disclosure.
Homology Independent Targeted Integration (HITI)
Applicant’s claim requires knock-in by a mechanism of homology independent targeted integration (HITI).
Applicant is directed to the art of record of Suzuki et al. (J Hum Genet. 2018 Feb;63(2):157-164. ; see IDS filed 22nd, May, 2023; henceforth “Suzuki”). Suzuki evidences that To translate HITI technology into a clinical application (i.e. the claimed “in a human subject”) several major barriers must still be overcome including efficiency (pg. 162-163 “Challenges for clinical translation”). Suzuki evidences that although the current HITI technology can insert DNA at a chosen target site in many non-dividing tissues, its efficiency is less than 5% in most cases and to use HITI technology to treat diseases in the clinic will require much higher gene-correction efficiencies (pg. 162-163 “Challenges for clinical translation”). Suzuki evidences it is still unclear how frequent and where ectopic DNA fragments integrate into non-target loci and the types of genetic defects that HITI technology will be able to treat is limited (pg. 163 col. 1 1st para.).
Further, as of the effective filing date of the claimed invention, the state of the art appears silent to any specific examples of HITI based methods in vivo in human subjects.
Even looking at the state of the art post-filing, there do not appear to be an any specific examples of HITI based methods in vivo in human subjects.
Therefore, because the art of Suzuki evidences that the challenges to translate murine data to a human subject are not predicable, applicant’s Examples in mice do not enable a HITI-based method in humans.
Timing of Administration
While Applicant’s claim encompasses all possible timings of delivery of the required components, Applicant’s examples are drawn to administration specifically at postnatal day 1 (p1), well before the retinal circuit is considered “complete” at p21.
Applicant is directed to the art of Orlans et al. (Hum Gene Ther. 2020 Jul;31(13-14):730-742. Epub 2020 Jun 26.; henceforth “Orlans”). Orlans evidence’s that late timing of gene therapy intervention in the RhoP23H/+ mouse may result in low therapeutic efficacy (abstract). Orlans evidences that a reconstitution of rod OS following subretinal RHO-AAV injection at postnatal day (P0) was accompanied by a modest rescue of the rod-derived ERG (pg. 737 col. 2 last para.). Orlans evidences similar reconstitution of OS with appropriate trafficking of transgenic wild-type human rhodopsin is
achievable following injection at PNW3, that is, after the point of terminal rod differentiation pg. 737 col. 2 last para.). Orlans evidences when applying gene therapy long after the outer segments (OS) develop, the ability for the outer nuclear layer (ONL) to regrow OS against all the forces of retinal adherence would likely be compromised to some extent, which might limit the volume of the OS generation (pg. 739 col. 2). Orlans evidences that when gene therapy is applied later in the disease there are fewer surviving rod photoreceptors to be transduced and express protein (pg. 739 col. 2). Orlans evidences any patient who is to undergo gene therapy treatment for rhodopsin-related ADRP
is likely to have long established disease at the point of intervention (pg. 741 col. 1 1st para.) Orlans evidences that when animals were injected after weaning at PND21 and not at earlier time points when
fewer rods would already have degenerated, the study failed to impart a measurable benefit (pg. 741 col. 1 1st para.).
Orlans further evidences that the RhoP23H/+ model undergoes more rapid retinal degeneration than the human disease it models (abstract; see also pg. 740 col 1 to pg. 741 col. 1 1st para.)
Therefore, because the state of the art evidences that timings after P21 (retinal circuit maturation), do not predictably result in a measurable benefit, Applicant is not enabled for all timepoints of administration.
Unpredictability of the Art and the Quantity of Experimentation
As the state of the art above demonstrates, the obstacles that hinder the use of the claimed method in human subject embodiments are not easy tasks to be done or solely routine experimentation to enabled particular embodiments of the claimed method. The type of experimentation would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the instant broadly claimed invention.
Enablement - Conclusion
In conclusion, the claims are not enabled because the specification provides limited working examples in a mouse model. The art at the time of effective filing fail to provide specific guidance that supplement to shortcomings of the specification in human subjects and further teaches that the breadth of claims cannot predictably be performed. Further, a great deal of new methodology would need to be developed to enable the claims and this level of experimentation is undue.
Response to Arguments
Applicant’s amendments to human subjects necessitated the new grounds of rejection above because the claims are not enabled. For the sake of compact prosecution, arguments considered pertinent to the new grounds of rejection are addressed below.
Applicant’s arguments, filed 5th, August, 2025, have been fully considered but are not found persuasive.
Applicant argues “the art is such that Applicant's adRP mouse model is recognized as correlating to adRP and should be accepted as supporting and enabling Applicant's in vivo method of treating.
M.P.E.P. § 2164.02(11)” (pg. 8-9; also pg. 10 last para.).
In response, although Applicant’s mouse model is an art recognized model of the symptoms and disease of adRP, it does not remedy the issues of enablement above because the state of the art indicates that translation of the claimed method from mouse to humans in unpredictable for the reasons stated above.
Applicant argues “Applicant's adRP mouse model is recognized as correlating to adRP and should be accepted as providing enabling support for Applicant's in vivo method of treating adRP in human subjects in the absence of any specific evidence to the contrary. M.P.E.P. § 2164.02(11)” (pg. 10 last para.).
In response, the Examiner has cited evidence to the contrary in the new grounds of rejection under 35 U.S.C. 112a Enablement above.
Applicant argues “Applicant's specification, in view of the art at the time of filing, provides sufficient information for a POSITA to identify, design, and utilize effective guide RNAs within the claimed scope” (pg. 13).
In response, in the new grounds of rejection above, evidence is cited in the art that translation of guide RNA design from mouse to humans is not predictable and therefore applicant is not enabled (see “Guide Molecule (gRNA) Design for Mice versus Humans“ Section of Enablement rejection above).
Applicant argues “the Office failed to provide any explanation as to why a POSITA would be unable to predict treatment of adRP, including alleviating or ameliorating symptoms of adRP. Action at 11” (pg. 13).
In response, because the method is unpredictable, for the reasons stated above, any alleged result obtained by the method is also unpredictable.
Applicant argues “The key requirement is that the patent specification must describe the claimed invention in sufficient detail to enable a POSITA to make and use the invention without undue experimentation. Applicant's specification is required only to impart to a POSITA the ability to practice "the invention as defined by its claims"-it is not necessary to maintain or achieve target results in order to practice the claims. Amgen Inc. v. Sanofi, 598 U.S. 594, 610 (2023).”
In response, instant claims require the result of “treating autosomal dominant retinitis pigmentosa in a human subject.” Because instant claims recite the functional result, it is the “invention as defined by its claims” and is necessary to make and use the invention
Examiner’s Remark
The examiner notes that the 35 U.S.C. 112a Written Description and Scope of Enablement rejections present in the previous office action have been withdrawn in view of Applicant’s amendments and new Grounds of rejection under 35 U.S.C. 112a Enablement and Written Description are set forth above in view of these amendments. For the sake of compact prosecution, the Declaration under 37 CFR 1.132 is addressed below as it applies to the present rejections of record.
Response to Declaration under 37 CFR 1.132
The Declaration under 37 CFR 1.132 filed 5th, August 2025 is insufficient to overcome the rejection of claims 15-18, 21-25, and 27-31 based upon 35 U.S.C. 112a Enablement and Written Description as set forth in the present Office action because although the RhoP23H/+ model is an art recognized model for adRP, there is evidence in the state of the art that it would not correlate for the claimed method for the reasons stated above. Summarized here in brief, the claims still lack written description support because specific guide molecule design is required for specific species and application types, and this cannot be envisioned from the disclosure or the art (see claim rejections under 35 U.S.C. 112a Written Description above), and the claims as currently presented art not enabled because CRISPR-Cas methods are not predictably translatable from mice to humans, guide molecule design is not predictable from mice to humans, HITI methods specifically are not predictable for clinical translation, and timings of administration are not predictable for treatment of adRP.
Claim Rejections - 35 USC § 112d
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 18 recites “the vector comprising the exogenous nucleic acid encoding the knock-in cassette further comprises a nucleic acid encoding the guide molecule for the Cas nuclease.” However claim 1, upon which claim 18 ultimately depends, already recites the viral vector encodes “a guide molecule to direct the Cas nuclease to a 5' UTR of an endogenous nucleic acid encoding the mutated RHO gene variant.” Therefore, claim 18 cannot further limit the claims upon which it depends because the guide molecule is already a required element of the claims before it is recited in claim 18.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Pertinent Art
The prior art of Diner et al. (WO-2020176552-A1; henceforth “Diner”). Made of record but not relied upon is considered pertinent to Applicant’s disclosure.
Diner teaches CRISPR/RNA-guided nuclease-related compositions and methods for treatment of RHO-associated retinitis pigmentosa (abstract). Diner teaches targeting the 5’UTR (pg. 2 line 25-26 “In certain embodiments, a 5' region of the RHO gene (e.g., 5' untranslated region (UTR), exon 1, exon 2, intron 1, the exon 1/intron 1 border or the exon 2/intron 1 border) is targeted by an RNA-guided nuclease to alter the gene). Dine teaches human subjects (pg. 27 line 12).
Diner does not teach homology-independent targeted integration into the 5' UTR.
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632