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 .
Claims status
Applicants reply filed 1/26/2026 is acknowledged.
Claims 8,20, 32 is/are cancelled. Claims 1-3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28, 31, 35, 36 is/are currently pending with claims 31, 35 and 36 is/are withdrawn. Claims 1-3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28 is/are under examination.
Claim Rejections - 35 USC § 112(b) – New, necessitated by claim amendments
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.
Rejection of Claims 13, 20 and 28 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of claim amendments and/or cancellation.
Claims 1-3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28 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.
Claim 1 is amended to recite “wherein the viral vector is an adeno-associated virus” in line 14. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 1 is/are interpreted as recite “wherein the first or second viral vector is an adeno-associated virus”.
Claim 1 is amended to recite “the split intein” in line 22. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 1 is/are interpreted as recite “the
Claims 2, 3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28 is/are rejected due their dependence on claim 1 because they do not clarify the 112b issue noted with claim 1.
Claim Rejections - 35 USC § 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.
Written Description – Maintained, updated to address claim amendments
Rejection of Claims 8, 20 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 is moot due to claim cancellation.
Claims 1-3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28 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.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claim 1 is a gene therapy method that embraces any Cas9 endonuclease wherein the Cas9 is split into any two fragments, one comprising the N-terminus and the other comprising the C-terminus (a N- and a C-terminal fragment in (a)(i) and (b)(i) respectively). The method requires reconstitution of the functional Cas9 as a result of the ligation of the any two fragments due to the functional association between two fragments of an intein. The claim also embraces any intein wherein the intein is split into any two fragments, one comprising the N-terminus and the other comprising the C-terminus (a N- and a C-terminal fragment in (a)(ii) and (b)(ii) respectively).
Claim 2 limits the endonuclease of claim 1 to SpCas9 but continues to embrace any two fragments of this SpCas9. Furthermore, Claim 2 does not limit the intein or its fragments.
Claim 3 limits the N- and the C-terminal fragment of the Cas9 of claim 1 to sequences that embrace sequences that are less than 100% identical to SEQ ID NOs: 2-5, for example sequences that are only 60% identical. This claim does not limit the intein or its fragments.
Claim 5 limits the intein of claim 1 to any one of the following inteins: Npu, NrdJ-1 or gp-41 or sequences that are less than 100% identical, for example sequences that are only 60% identical, to SEQ ID NOs: 6-8 which are full length sequences for Npu, NrdJ-1 or gp-41 respectively. Furthermore, the claim embraces any two fragments of the recited sequences. This claim does not limit the endonuclease or its fragments.
Claim 6 limits the N- and the C-terminal fragment of the intein of claim 1 to sequences that embrace sequences that are less than 100% identical, for example sequences that are only 60% identical, to SEQ ID NOs: 9-11, 12-14. This claim does not limit the Cas9 endonuclease or its fragments
Claim 11, 13, 16, 17, 22, 24-26, 28 do not limit the Cas9 endonuclease or the intein or their fragments and, thus embrace the same broadly claimed structures as claim 1.
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 if). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G. D. Searie & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004). See MPEP § 2163.
In the instant case, the specification discloses only Cas9 endonuclease from Streptococcus pyogenes that could be fragmented and reconstituted i.e. generate a functional endonuclease, as required by the claim. Only two sites for fragmentation are disclosed for this specific Cas9: between either amino acid residues 573/574 or 637/638 [77]. This results in two species for the N-terminal fragment (SEQ ID NO: 2, 3) and two species for the C-terminal fragment of SpCas9 (SEQ ID NO: 4, 5) [78-79]. No other site for fragmentation is disclosed. Therefore, the specification does not disclose any Cas9 endonuclease, other than SpCas9, and any fragments, other than SEQ ID NOs: 2-5 that are fragments of SpCas9. Critically, no structural or functional identifying features that allows for identification of sites in an Cas9 endonuclease, amenable for the recited function of fragmentation and reconstitution are disclosed.
Regarding sequences less than 100% identical to SEQ ID No: 2-5, although the specification prophetically states that the sequences that are less than 100% identical to SEQ ID No: 2-5 could be used as fragment [78-79], there is no disclosure supporting that sequences that are less than 100% identical to SEQ ID No: 2-5 would result in fragments that are capable of reconstituting into a functional endonuclease, as required by the claim. In other words, a skilled artisan cannot envision the structure of fragments that are less than 100% identical to SEQ ID No: 2-5 that could be used as fragments capable of reconstitution in vivo, as required by the claim.
Split enzyme designs were known to a skilled artisan however identification of split sites that allow for generation of enzyme fragments that are stable and functional are critical to this process because “hydrophobic surfaces that are exposed when an enzyme is fragmented can cause low stability, aggregation, or non-specific interactions and compromise the effectiveness of the split enzyme” (See section: 2.3 Split fragments are generally less stable than the original enzyme in Lim et al, Chapter 12 in Methods in Enzymology, Volume 644, 2020; ref of record). To this end, no split sites for endonucleases as broadly claimed, other than the two sites for SpCas9, have been disclosed in the specification. Furthermore, even for SpCas9, no split sites other than the two sites have been disclosed. These two sites required careful consideration and cannot be easily replaced with any other split site. Split Cas9, same as the instant application, were first disclosed by Truong et al (Nucleic Acids Research, 2015, Vol. 43, No. 13; ref of record). Truong discloses that “The split-sites of SpCas9 were carefully chosen between Glu573 and Cys574 for the first version (v1) or between Lys637 and Thr638 for the second version (v2), since the N-terminal amino acid of the C-Cas9 in the C-Intein_C-Cas9 fusion should be Cys, Ser or Thr to ensure high splicing efficiency (7,25) (Figure 1a).Moreover, particular attention was given such that the split-sites were surface-exposed due to the sterical need for protein splicing (26).” (emphasis added, See section: Design of Intein-mediated split SpCas9). Therefore, considering the requirements for split enzyme design, sufficient disclosure of structures of Cas9 endonucleases amenable to fragmentation and sites within the broadly claimed genera of Cas9 endonucleases that are amenable to fragmentation are required for a skilled artisan to envision the structures of the fragments of endonucleases capable of functionally reconstituting as a functional endonuclease, as claimed.
Similar issue arises for inteins and their fragments as broadly claimed.
The specification defines “intein” as “protein introns, which are able to auto catalytically splice themselves posttranslationally out of a protein resulting in covalently linked exteins as a scar less gene product” [68] and “functional intein” as “capable of ligating the first and the second fragment of a protein” [70]. Considering the claim requires the recited intein to be split into two fragments, one comprising an N-terminal and the other a C-terminal, that function together to perform the ligation of the endonuclease fragment, the claim is directed towards a sub-genus of inteins called split inteins. The specification discloses that split inteins are “a subset of inteins that are expressed in two separate halves” and have “unique properties” that “offer improved controllability, flexibility and capability to existing tools based on contiguous inteins” [69].
For the broadly claimed genera of inteins and their fragments, the specification discloses three natural split intein species Npu, NrdJ-1 and gp41-1 that each have only one set of fragments that are capable of functioning together to perform the ligation function required by the claim [74]. The specification discloses the structures of these split intein fragments (SEQ ID NOs 9-14) [74]. No other fragments for the disclosed split inteins are taught. Therefore, the specification does not disclose any intein, other than split intein, and any fragments, other than SEQ ID NOs: 9-14 that are known fragment sets for three disclosed split inteins. Critically, no structural or functional identifying features that allows for identification of fragments in an intein, including other fragments of disclosed split inteins, amenable for the recited function of ligation are disclosed.
Regarding sequences less than 100% identical to SEQ ID No: 6-14, although the specification prophetically states that the sequences that are less than 100% identical to SEQ ID No: 6-14 could be used as inteins and/or their fragments [74], there is no disclosure supporting that sequences that are less than 100% identical to SEQ ID No: 6-14 would result in fragments that are capable of ligation required to form the functional endonuclease. In other words, a skilled artisan cannot envision the structure of fragments that are less than 100% identical to SEQ ID No: 6-14 that could be used as fragments capable of ligation in vivo, as required by the claim.
Use of split inteins in split enzyme design was known (for example in Truong) however split sites in both naturally occurring split inteins and engineered split inteins are tightly regulated. Sun et al (JBC, Vol. 279, No. 34, 2004; ref of record) teaches that “Interestingly, all these DnaE split inteins share the same split site, which may be explained by a single origin for all these split inteins. However, it may also suggest that splitting at any other site is incompatible with protein trans-splicing and therefore not tolerated, which can be examined by splitting inteins at other sites followed by testing for possible trans-splicing. Synthetic two-piece split inteins have been engineered before in laboratories by splitting the coding sequences of contiguous inteins, but their split sites corresponded with those of the naturally occurring split inteins” (emphasis added, pg 35281, col. 2, para 2). Herein, Sun attempted to identify new split sites in a contiguous SspDnaB intein by focusing only on sites in the “loop regions between the b-strands” of this intein (pg 35282, col. 1, last para). Although 4 out 13 sites tested in these specific regions of the intein did allow for ligation, no structural feature was identified that predictable produced fragments capable of ligation (Figure 2). To this end, Sun notes that “Not all split sites in a loop region produced trans- splicing activity, indicating that some loop sequences cannot be broken, possibly because they are required to hold the flanking b-strands in correct conformation” (pgs 35284-35285, bridging para). Therefore, considering a lack of identifying features for a split site in an intein, sufficient disclosure of structures of inteins amenable to fragmentation and sites within the broadly claimed genera of inteins that are amenable to fragmentation are required for a skilled artisan to envision the structures of the fragments of inteins capable of functionally ligating the endonuclease fragments, as claimed.
Taken together, the claimed invention, as a whole, is not adequately described. The claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art before the effective filing date.
Further, the breadth of the genus of endonucleases capable of fragmentation, fragments of endonucleases capable of reconstitution, inteins capable of fragmentation and fragments of inteins capable of ligation lack a written description.
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 Deutschland 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 the instant case, considering several Cas9 endonucleases are known in the art and there is no claimed limitation on fragmentation site, the claims embrace an extremely broad and highly structurally variable genus of any fragment of any endonuclease with the only limitation being that one fragment comprises an N-terminus while the other comprises a C-terminus. Yet, only a single species of Cas9 is disclosed for the genus of Cas9 endonucleases capable of fragmentation and only two set of fragments are disclosed for the genus fragments of Cas9 endonucleases capable of reconstitution. Similarly, the claims embrace an extremely broad and highly structurally variable genus of any fragment of any inteins with the only limitation being that one fragment comprises an N-terminus while the other comprises a C-terminus, while disclosing only three species, each of split inteins and each with known split fragments. Additionally, the claims also embrace species with sequences that are less than 100% identical to the known-disclosed sequences without providing identifying characteristics that disclose a correlation between function and structure.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the recited genera.
Scope of Enablement– New, necessitated by claim amendments
Rejection of Claims 18 and 20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the scope of enablement requirement is moot due to claim cancellation.
Rejection of Claims 1-3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the scope of enablement requirement is withdrawn due to claim amendments that are now addressed in the scope of enablement rejection below.
Claims 1-3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification,
while being enabling for
A method of treating Duchenne muscular dystrophy (DMD) in a subject in need thereof, the method comprising intravenously or intramuscularly administering an AAV viral vector system to said subject at an effective dose, the AAV viral vector system comprising
(a) a first AAV viral vector coated with a dendrimer, the first AAV viral vector comprising a nucleic acid sequence encoding:
(i) an N-terminal fragment of Cas9 endonuclease comprising the sequence of SEQ ID NO: 2 or 3,
(ii) an N-terminal fragment of an split intein comprising the sequence of any one of SEQ ID NO: 9-11, and
(iii) a first guide RNA (gRNA); and
(b) a second AAV viral vector coated with a dendrimer, the second AAV viral vector comprising a nucleic acid sequence encoding:
(i) a C-terminal fragment of the Cas9 endonuclease comprising the sequence of SEQ ID NO: 4 or 5,
(ii) a C-terminal fragment of the split intein comprising the sequence of any one of SEQ ID NO: 12-14, and
(iii) a second guide RNA (gRNA);
wherein the first gRNA binds to a region located 5' to a sequence of interest comprised in a nucleic acid sequence in a dystrophin gene of a target cell,
wherein the second gRNA binds to a region located 3' to the sequence of interest comprised in the nucleic acid sequence in the dystrophin gene of the target cell;
wherein administration of first and second AAV viral vectors results in association of the N-terminal fragment and the C-terminal fragment of the split intein into a functional intein,
wherein the functional intein ligates N-terminal fragment and the C-terminal fragment of the Cas9 endonuclease together to form a functional Cas9 endonuclease;
wherein the functional Cas9 endonuclease excises the sequence of interest from the nucleic acid sequence in the dystrophin gene; and
wherein the administration results in production of functional dystrophin protein in the cardiac muscle cells and skeletal muscle cells of the subject.,
does not reasonably provide enablement for a method that treats DMD using a lentivirus vector for delivery of the CRISPR reagents or wherein the AAV or the lentivirus vector are administered by any means at any dose. Additionally, use of any fragments of any Cas9 endonuclease and use of any fragments of any inteins is not enabled in a method for treating DMD.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the vectors and use the vectors in a method of treatment that is commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: the claims as currently drafted encompass methods of treating DMD by administering an AAV or lentivirus based vector system, wherein the vector system is administered via any route/means of administration at any dose. The vector system also encompasses any fragments of any Cas9 endonuclease, any fragments of any inteins. Functional limitations such as requirement of intein fragments to ligate endonuclease fragments to form a functional endonuclease are recited however, as noted in written description rejection above, insufficient disclosure is provided for structures capable of these functions. Additionally, these features lack enablement. Consequently, the breadth of the claims is broad.
(B) The nature of the invention: The invention is in the field of gene therapy by delivery of an AAV vector comprising sequences encoding split Cas9 enzyme with two gRNAs that excise a sequence from the dystrophin gene associated with frameshift mutation that results in recovery of the open reading frame of the dystrophin gene and thus production of a functional dystrophin gene product.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: As detailed in the written description rejection, use of specific fragments of split inteins in engineering split enzymes was known in the art as taught by Sun. However, no predictable structural feature of split sites that is related to production of functional intein fragments was known (See discussion from Sun above). Similarly, split enzymes and specifically split spCas9 enzyme with inteins was also known in the art. As taught by Lim as well as Truong. However, again no predictable structural feature of split sites that is related to production of functional endonuclease fragments was known (See discussion from Lim and also from Truong above). Lim specifically notes that “It is still difficult to rationally select specific functional and stable fragmentation sites” (pg 292).
Therefore, generation of split inteins and endonucleases wherein the inteins and endonuclease are split into any two fragments is not taught by the art and a skilled artisan cannot predictable generate such split inteins and endonucleases, as embraced by the claims.
In addition to requiring the high skill of functional enzyme engineering, the claim also requires the use of these broadly claimed split enzymes in an in vivo gene therapy method to treat DMD. Use of CRISPR-Cas based gene therapy for DMD wherein a sequence of interest is excised, the prior art teaches the use of AAV vectors to deliver Cas enzymes along with the sgRNAs targeting mutated exons in the dystrophin gene wherein the AAV vector is delivered to the muscles of the animal either by intramuscular or intravenous delivery method. Tabebordbar et al (Science, Vol. 351, 2015; ref of record) teaches intravenous and intramuscular delivery of AAV9 encoding Cas9 and two guide RNAs that result in excision of mutated exon 23 of DMD gene (Figure 2, 3). Similarly, Bengtsson et al (Nature Comm., 8:14454, 2017; ref of record) also teaches only intravenous and intramuscular delivery of AAV6 encoding Cas9 and two guide RNAs that result in excision of mutated exons 52-53 of DMD gene (Figure 1, Methods: Animals). Similar methods are taught by Mali et al (WO 2018/035503 A1, 22 February 2018; ref of record; See Figure 23), Nelson et al (Science, Vol 351, 2015; ref of record; See Figure 1) and El Refaey et al (Circulation Res, Vol. 121, 2017; ref of record; See Figure 1). However, the prior art fails to teach a gene therapy method for DMD wherein an AAV vector was delivered by any means other than intramuscular or intravenous or wherein a lentiviral vector was used to deliver the CRISPR agents.
Successful gene therapy requires therapeutically effective expression of the transgene in appropriate tissues depending on the pathology.
For AAV based vector systems, a combination of factors such as at least AAV serotype, mode of administration and promoter affect transgene expression. Mingozzi et al (Nature Reviews Genetics, Volume 12, May 2011; ref of record) teach the challenges to clinical use of AAV are generally tissue specific and target tissue not only differ with respect to response to immune injury due to AAV transduction but also optimal mode of gene delivery (page 341, right column, para 2). Promoter choice is important because it could determine gene silencing in the target tissue (Box 1; gene silencing) and AAV capsid when combined with means of delivery can affect immunotoxicity (Box 1; immunotoxicity). Regarding the challenges in gene therapy, Mingozzi state that “Gene transfer strategies can be described in terms of three critical elements: the vector or gene delivery vehicle; the transgene; and the target tissue. Given that human immune responses are a major hurdle for in vivo gene transfer and that many aspects of the human immune response are tissue-specific, it is perhaps not surprising that each target tissue constitutes its own set of challenges for in vivo gene transfer. Following from this, solutions that enable gene transfer for one target tissue may not easily translate to others. As an additional layer of complexity, vector delivery to the same tissue but by a different route of administration may present a different set of obstacles. For example, gene delivery to skeletal muscle by direct intramuscular injection does not seem to be impeded by circulating antibodies to vectors 39,148, whereas vectors delivered to muscle via the vascular tree must somehow evade the effects of neutralizing antibodies 8,36,111. Finally, depending on the target tissue, immune responses to either the transgene product or to the vector may predominate, highlighting another issue that must be carefully addressed to achieve optimal results in the clinical setting.” (Box 3; emphasis added). Issa et al (Cells 2023, 12, 785; ref of record) is a post-filing review of AAV base gene therapy providing a more up to date review of AAV serotypes, their organ/tissue specificity (i.e. tropism) and continued challenges in identifying mechanisms of AAV targeting that would allow for more predictable use of pre-clinical models across species. Issa state that “Another challenge is the need to deeply understand the exact mechanisms and pathways of AAV cellular uptake, trafficking, and transduction, which are still unknown for most AAV serotypes [367]. Such understanding can help in addressing and explaining the changes of transduction potency and efficacy that can be found between different species in different in vivo studies, or between treatment efficacy in vivo and in clinical trials [368]. In other words, differences between humans and various animal models in terms of body size, genomic and anatomic specificity, immunogenicity, and disease process should be taken into account, as they can affect the effective translation of preclinical investigations” (page 16, para 2) and “AAVs were discovered over five decades ago and have since represented a potent tool for gene therapy, that still needs to be better understood and developed for broader and larger therapeutic applications. Further optimizations should cover vector design, tropism modifications, and delivery routes” (Conclusion).
Taken together, AAV serotype, promoter and mode of administration each effect the tissue targeted by the gene therapy which in return affects the expression of the transgene required for a therapeutic method. Although use of AAV based gene therapy is fairly advanced, several sources of unpredictability remain.
For lentivirus based vector systems, Milone et al (Clinical use of lentiviral vectors. Leukemia (2018) 32:1529–1541) teaches that lentiviral vectors are being used for ex vivo gene transfer to cells for cell therapy application (page 1535, col. 1, para 2; page 1536, col. 1 para 1) however in vivo use of lentiviral vectors for gene therapy applications “These approaches face a number of hurdles including efficiency, need for tissue-restricted promoters, and immunogenicity. The latter is particularly important since immunogenicity can be related to both the delivered gene as well as components of the vector. As discussed earlier, the lentiviral vector envelope captures membrane proteins from the packaging cell lines during the budding process. Alloimmune reactivity towards HLA class I proteins carried within the vector envelope have been described and can limit vector survival. Gene editing of packaging cells to generate lines that lack HLA class I can enhance the stability of lentiviral vectors in serum [81]. Surface engineering in addition to vector genome engineering will likely be critical for successful application of these vectors in vivo.” (page 1536, col. 1, para 2). Thus, use of lentiviral vectors for in vivo gene therapy is currently not enabled based on the prior art, requiring additional experimentation to first develop a lentiviral vectors that could be used for such methods.
An enabling disclosure for a method, as broadly claimed, would require guidance regarding lentiviral and AAV vectors in combination with modes of administration that effectively deliver the transgene to target tissue and guidance regarding the structure of split endonucleases and split inteins that comprise any two fragments as claimed.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: The applicants have provided working examples directed to treatment of DMD i.e. a disease with frameshift mutation in dystrophin gene [132-133, 141, 143, Example 1].
In [81], the specification prophetically discloses viral particles as vectors, suggesting the use of either AAV, a non-integrating ssDNA viral vector, or lentiviral vector, an integrating ssRNA viral vector. Same as the prior art, the working examples are limited to AAV vectors (Example 1). The applicants have not provided working examples for use of lentiviral vectors for gene therapy, especially for the delivery of gene editing CRISPR reagents for the treatment of DMD.
In Claim 25 and [104], the specification prophetically discloses several modes of administration such as “systemic, enteral, parenteral, intravenous, intra-arterial, topical, intraperitoneal, intramuscular, intradermal, intrathecal, intravitreal, subcutaneous, transdermal and/or transmucosal administration”. Same as the prior art, the working examples are limited to systemic i.e. intravenous/intraarterial and intramuscular modes only [139-140]. The applicants have not provided working examples for the use of other modes of administration for AAV or lentiviral vectors, such that optimal therapeutically-efficacious expression of the CRISPR reagents could be achieved for the treatment of DMD.
Finally, as noted in the written description rejection above, the guidance in the specification regarding structures of fragments of split intein and split endonucleases is limited to SEQ ID NOS: 9-14 (i.e. known fragments of Npu, NrdJ-1 and gp-41) and SEQ ID NOs: 2-4 (i.e. known fragments of SpCas9), respectively. The working examples are limited to the use of split SpCas9 at residue 573 (SEQ ID NOs: 2, 4) along with Npu split intein fragments (SEQ ID NOs: 9, 12) (Figure 5). The applicants have not provided description of other fragments of split endonucleases and split inteins.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the broad breadth of the claims, the state of the prior art and its unpredictability, and the limited amount of guidance in the form of varied working examples in the specification.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
After applying the Wands factors and analysis to claims 1-3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher decisions discussed above, it is concluded that the practice of the claimed invention to its entire scope would not be enabled by the written disclosure. Therefore, claims 1-3, 5, 6, 11, 13, 16, 17, 22, 24-26, 28 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to make and use the claimed invention to its full scope.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Rejection of Claim(s) 8, 20 under 35 U.S.C. 103 as being unpatentable over Mali et al (WO 2018/035503 A1, 22 February 2018; IDS 11/29/2023) is moot due to claim cancellation.
Rejection of Claim(s) 1, 2, 3, 5, 6, 11, 16, 17, 22, 24, 25 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mali et al (WO 2018/035503 A1, 22 February 2018; IDS 11/29/2023) is withdrawn because Mali does not teach dendrimers.
Rejection of Claim(s) 13 under 35 U.S.C. 103 as being unpatentable over Mali as applied to claim 1, 8 above, and further in view of Abedi-Gaballu et al (Appl Mater Today. 2018 September ; 12: 177–190. Hereinafter Abedi) and Vetter et al (Mol. Pharmaceutics 2013, 10, 606−618; IDS 11/29/2023) is withdrawn because of withdrawal of previous rejection of claim 1 and 8.
Rejection of Claim(s) 28 under 35 U.S.C. 103 as being unpatentable over Mali as applied to claim 1 above, and further in view of Amoasii et al (Science 362, 86–91 (2018); IDS 11/29/2023) and NG_012232.1 (Human DMD gene sequence provided by RefSeq Dec 2016) is withdrawn because of withdrawal of previous rejection of claim 1 and 8.
Claim(s) 1, 2, 3, 5, 6, 11, 13, 16, 17, 22, 24, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mali et al (WO 2018/035503 A1, 22 February 2018; ref of record) and Vetter et al (Mol. Pharmaceutics 2013, 10, 606−618; ref of record)) in view of Abedi-Gaballu et al (Appl Mater Today. 2018 September ; 12: 177–190. Hereinafter Abedi; ref of record)) as evidenced by Zincarelli et al (Analysis of AAV Serotypes 1–9 Mediated Gene
Expression and Tropism in Mice After Systemic Injection. Molecular Therapy vol. 16 no. 6, 1073–1080 june 2008).
Regarding claims 1, 2, 5, 20 and 26, Mali teaches a method of treating Muscular dystrophy associated with dystrophin gene i.e. DMD (=treating DMD, as required by claim 26; [0028, 0181]). Mali’s method comprises administering an AAV viral vector system comprising two AAV vectors (as required by a, b); [0036], [0057], Figure 2, Figure 23). In Mali’s dual-AAV system, the first vector comprising a C-Cas9 fragment of SpCas9 endonuclease and C-intein fragment of Npu split intein (= claimed b(i) and b(ii) C-terminal fragment of Cas9 with C-terminal fragment of intein; [0010], [0133]) and a second vector comprising a N-Cas9 fragment of SpCas9 endonuclease and N-intein fragment of Npu split intein (= claimed a(i) and a(ii) N-terminal fragment of Cas9 with N-terminal fragment of intein; [0010], [0133], [0240], Figure 2) (SpCas9 as required by claim 2 and Npu as required by claim 5). Considering Mali’s vector system comprises functional intein fragments and Cas9 fragments, Mali’s system results in a system wherein upon administration intein fragments associate to form functional intein that ligate Cas9 fragments to form a functional Cas9, as required by claim 1. Specifically, Mali teaches that coexpression of the two vectors results in the expression of the whole functional Cas9 protein [0010, 0135, 0240].
In the method of treating DMD, Mali teaches a dual gRNA approach where the gRNAs are designed to target up and downstream of exon 23, the sequence of interest in DMD, resulting in excision of mutated exon 23 (= claimed first gRNA binding 5’ and second gRNA binding 3’ of sequence of interest, excision of sequence of interest, as required by claim 1); [0057], Figure 23).
Furthermore, Mali teaches the use of various AAV vector, specifically teaching intravenous AAV8 in Figure 23. Zincarelli evidences that AAV8 vectors when delivered intravenously result in transgene expression in the heart and skeletal muscle (Figure 2, 4). Therefore, Mali’s method results in excision of mutated exon 23 of dystrophin gene and thus production of functional dystrophin protein in the heart and skeletal muscle.
Mali does not explicitly teach the location of the two gRNAs in their dual AAV vector system. In other words, Mali does not explicitly teach if the two gRNAs are arranged such that only one gRNA is located on each vector such that the first gRNA is on the first vector while the second gRNA is on the second vector, as required by claim 1a(iii), b(iii).
However, Mali teaches that “It should be appreciated that the effector elements disclosed herein may be configured in a variety of ways depending on the space available in each of the two vectors in the recombinant expression system disclosed herein” [0190]. Thus, Mali suggests that the two gRNAs could be located together on one of the two vectors in their dual AAV-system or located separately i.e. only one gRNA per vector, as claimed.
The arrangement of the two gRNAs on the same or different vectors is rearrangement of parts without patentable distinction. In re Japikse, 181 F.2d 1019, 86 USPQ 70 (CCPA 1950) (Claims to a hydraulic power press which read on the prior art except with regard to the position of the starting switch were held unpatentable because shifting the position of the starting switch would not have modified the operation of the device.) (See MPEP 2144.04 V). In the instant case as well, shifting the location of the two gRNAs would not modify the functional outcome of the method since under both circumstances, the gRNAs would target their respective target sites flanking the sequence of interest which would be excised only by the reconstituted functional Cas9 endonuclease which are explicitly present on separate AAVs. Therefore, in teaching a method comprising a dual AAV-system comprising two gRNAs, Mali renders the instantly claimed dual AAV-system wherein the gRNAs on separate vectors prima facie obvious.
Mali also teaches the limitations presented in claims 2, 3, 5, 6, 11, 16, 17, 22, 24 and 25.
Regarding claims 2 and 3, Mali teaches the sequence for N-Cas9 fragment and C-Cas9 fragment on pages 26-27 that are at least 60% identical to SEQ ID NOs: 2 and 4 and together form a SpCas9 endonuclease with a sequence at least 60% identical to SEQ ID NO: 1 (See Sequence alignment in PTO-892).
Regarding claims 5 and 6, Mali teaches the sequence for N-intein and C-intein from Npu on page 26-27 that are at least 60% identical to SEQ ID NOs: 9 and 12 and together form a Npu split intein with a sequence at least 60% identical to SEQ ID NO: 6 (See Sequence alignment in PTO-892).
Regarding claim 11, Mali teaches the use of various AAV vectors, including AAV8 and AAV9 [0017, 0057, 0059, Figure 23 and 25].
Regarding claim 16, Mali teaches the N-Cas9 fragment on page 27 that comprises a NLS sequence identical to SEQ ID NO: 15 (See Sequence alignment in PTO-892).
Regarding claim 17, Mali teaches the use of promoters for the expression of the Cas9 fragments, the intein fragments and promoters for the expression of the gRNAs ([0010, 0012, 0119, 0135, 0138-0144).
Regarding claim 22, Mali teaches administration of the two vectors in the dual vector system simultaneously [0233].
Regarding claim 24, Mali teaches a mammalian subject, including human [0032].
Regarding claim 25, Mali teaches the several means of administration, specifically intravenous [0057, 0223, 0233]
Although Mali teaches the use of AAV viral vectors for the delivery of the transgenes of claim 1, Mali does not teach coating the viral vector in a dendrimer.
Vetter teaches the method to coat viral vectors with PAMAM dendrimers (as required by claim 13; 2.5. Coating of Ad with PAMAM Dendrimer or LPEI and BPEI Polymer). Vetter also teaches the immunogenicity of viral vectors and the utility of PAMAM-coating in reducing the immunogenicity of viral vectors (Discussion, para 1).
Abedi teaches that it was known that AAV vectors induce immunogenic responses while low immunogenicity is associated with PAMAM-coated therapeutics (pages 10-11, bridging para).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to coat the AAV vector of Mali with PAMAM dendrimer, as taught by Vetter. Since Abedi teaches the immunogenicity associated with AAV vectors, an ordinary artisan would be motivated to coat Mali’s AAV vectors with PAMAM dendrimer to reduce their immunogenicity. An ordinary artisan would reasonably expect to coat Mali’s vector with PAMAM-dendrimer because Vetter teaches the method for coating vectors with PAMAM-dendrimer.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mali and Vetter in view of Abedi as applied to claim 1 above, and further in view of Klymiuk et al (Human Molecular Genetics, 2013, Vol. 22, No. 21); IDS 11/29/2023) and NC_010461.5
(Pig DMD gene sequence provided by RefSeq Jan 2018; PTO-892).
Regarding claim 26, the teachings from Mali, Vetter and Abedi detailed in the U.S.C. 103 rejection of claim 1 are pertinent.
Mali teaches the method wherein the DMD comprises a stop codon in exon 23 of the dystrophin gene and Mali targets sequences in exon 23 as the sequences of interest that are targeted to excise exon 23 to recover the dystrophin gene reading frame ([0057], Figure 23). Mali also teaches an alternative method wherein a single gRNA was used to alter the stop codon in exon 23 to recover the dystrophin gene reading frame (Figure 23, [0057].
Mali does not teach DMD comprising a deletion of exon 52.
Klymiuk teaches DMD that comprises deletion of exon 52 which results in a frameshift and premature stop codons in exon 53 and 54 (Abstract; page 4369, col. 1, last para).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use Mali’s method to restore the reading frame of the dystrophin gene in DMD that comprises deletion of exon 52, as taught by Klymiuk. An ordinary artisan would be motivated to use Mali’s method to restore the reading frame of the dystrophin gene in DMD that comprises deletion of exon 52 that results in introduction of premature stop codons because Mali teaches that their method can be used to restore reading frame of the dystrophin gene in DMD that comprises premature stop codons. An ordinary artisan would reasonably expect to apply Mali’s method to DMD that comprises a deletion of exon 52 that results in premature stop codon because Mali’s teaches methods to design gRNAs [0112, 151] which could be applied to design of gRNAs targeting exons with premature stop codons in Klymiuk’s DMD. Mali makes several gRNAs targeting various sequences (page 39, 41-46, 47-48, 50, 51, 52, Table 1). An ordinary artisan would reasonably generate gRNAs targeting exons with premature stop codons using Mali’s teachings and the sequence of DMD gene publicly available as NC_010461.5.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim(s) 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mali and Vetter in view of Abedi as applied to claim 1 above, and further in view of Amoasii et al (Science 362, 86–91 (2018); ref of record) and NG_012232.1 (Human DMD gene sequence provided by RefSeq Dec 2016; ref of record).
Regarding claims 28, the teachings from Mali, Vetter and Abedi detailed in the U.S.C. 103 rejection of claim 1 are pertinent.
Mali teaches the method wherein the DMD comprises a stop codon in exon 23 of the dystrophin gene and Mali targets sequences in exon 23 as the sequences of interest that are targeted to excise exon 23 to recover the dystrophin gene reading frame ([0057], Figure 23). Mali also teaches an alternative method wherein a single gRNA was used to alter the stop codon in exon 23 to recover the dystrophin gene reading frame (Figure 23, [0057]. Mali shows that the dual gRNA approach results in increased restoration of dystrophin protein expression in comparison to the single gRNA approach (Figure 23d).
Mali does not teach targeting sequences in exon 51 of the dystrophin gene as the sequence of interest.
Amoasii teaches that frameshift mutations in exon 45-50 of the dystrophin gene that could be treated by “skipping” exon 51 were known (page 1, col. 3, para 1). Amoasii teaches the alternate approach taught Mali wherein a single gRNA is used to alter the stop codon in exon 51 to recover the dystrophin gene reading frame (Figure 1).
NG_012232.1 is the sequences of exon 51 which is same as the SEQ ID NO. 23 (See Sequence alignment in PTO-892).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to target exon 51 of dystrophin gene in place of exon 23 using the two gRNA approach taught by Mali. An ordinary artisan would be motivated to target exon 51 using Mali’s two gRNA approach because Amoasii teaches that this exon could be targeted to recover the dystrophin gene reading frame in DMD frameshift mutations in exons 45-50 using a single gRNA approach and Mali teaches the dual gRNA is better than the single gRNA approach. An ordinary artisan would reasonably expect to target exon 51 of DMD gene using Mali’s two gRNA approach because the sequence of the entire DMD gene for many species was known, such as human was taught by NG_012232.1 and both Mali as well as Amoasii teach methods to design gRNAs to target sequence of interest (See [0112], [0169] in Mali and sgRNA identification, evaluation and cloning in Amoasii).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 1/26/2026 regarding the U.S.C. 112a – Written Description rejection of Claims 1-3. 5, 6, 8, 11, 13, 16, 17, 20, 22, 24-26, and 28 have been fully considered but they are not persuasive.
Applicants do not present separate arguments for the U.S.C. 112a – Written Description rejection and the U.S.C. 112a – Scope of Enablement rejection. Attempt is made to properly identify each argument pertinent to the U.S.C. 112a – Written Description rejection and is addressed below.
Applicant allege that the specification fully satisfies the written description requirement because it allegedly provides “working examples demonstrating actual reduction to practice, detailed structural disclosures, and explicit technical guidance” (page 11-12, bridging para).
In response, Applicant have not pointed out where in the specification detailed structural disclosures, explicit technical guidance and/or working examples demonstrating actual reduction to practice are present that support the claims that embrace structures comprising any fragment of any Cas9 endonuclease comprising an N-terminal, any fragment of any Cas9 endonuclease comprising a C-terminal, any fragment of any intein comprising an N-terminal, any fragment of any intein comprising a C-terminal. Not only is there no explicit structural details or working examples in the specification, there is no technical guidance regarding enzyme fragmentation, specifically sites in Cas9 enzymes as generically claimed, other than the two disclosed for SpCas9, that could provide guidance to an ordinary artisan to envision the structure of the various fragments embraced by the claims. Similar issue arises for the fragments of inteins.
Applicant also allege that the “The claims do not embrace the unlimited genera asserted by the Examiner. Rather, the claims define a therapeutically effective gene therapy method for DMD using split endonuclease-intein systems delivered by dendrimer-coated viral vectors to restore dystrophin expression, precisely the method disclosed and reduced to practice in, e.g., Example 1.” (page 14, para 2)
In response, the method reduced to practice in Example 1 is limited to SpCas9 fragments of SEQ ID NO. 2, 4 and Npu intein fragments of SEQ ID NO. 9, 12. This does not support the claims embrace of any fragment of any Cas9 endonuclease comprising an N-terminal, any fragment of any Cas9 endonuclease comprising a C-terminal, any fragment of any intein comprising an N-terminal, any fragment of any intein comprising a C-terminal. This example discloses one specie for the broadly claimed genera. Considering any fragment, that comprise an N- or a C-terminal, of any Cas9 and any intein are embraced by the claims, substantial variation between the embraced species exist such that disclosure of a singular species is not representative.
Applicant argue that the specification satisfies “actual reduction to practice, structural disclosure, or sufficient identifying characteristics” (page 14, para 3). In support, Applicant point to example 1 as allegedly showing of “actual reduction to practice” (page 14, last para). Applicant allege that the “The specification also provides extensive structural information, including Cas9 sequences and fragments, the three split intein species and their fragments, target sequences in the dystrophin gene, and gRNA sequences in addition to detailed exemplary vector architectures showing promoters, coding sequences, nuclear localization signals, and regulatory elements as well as validated coating parameters with comparative efficacy data. Besides reduction to practice and structural disclosure, the specification also provides extensive guidance on component selection and functional design such as fragmentation site selection criteria, intein mechanisms, gRNA design as well as vector administration using standard protocols with dose-finding data” (page 14-15, bridging para).
In response, as noted above, the method reduced to practice in Example 1 is limited to SpCas9 fragments of SEQ ID NO. 2, 4 and Npu intein fragments of SEQ ID NO. 9, 12. This does not support the claims embrace of any fragment of any Cas9 endonuclease comprising an N-terminal, any fragment of any Cas9 endonuclease comprising a C-terminal, any fragment of any intein comprising an N-terminal, any fragment of any intein comprising a C-terminal. This example discloses one specie for the broadly claimed genera. Considering any fragment, that comprise an N- or a C-terminal, of any Cas9 and any intein are embraced by the claims, substantial variation between the embraced species exist such that disclosure of a singular species is not representative.
Furthermore, as above, Applicant again have not pointed out where in the specification extensive structural information regarding the broadly claimed Cas9 fragments and broadly claimed inteins fragments could be found. As noted in the rejection above, the disclosure is limited to SpCas9 fragmented at residue 573 or 637 resulting in two sets of fragments of SEQ ID NO: 2, 4 and 3, 5. Similarly the disclosure is limited to Npu, NrdJ-1 and gp41-1 inteins that each have only one set of fragments (SEQ ID NOs 9-14). Structural information pertaining to any other fragments of SpCas9 and Npu, NrdJ-1 and gp41-1 inteins is lacking. Critically, the claim embraces Cas9 and inteins other than SpCas9 and Npu, NrdJ-1 and gp41-1 inteins. Structural information pertaining to any fragment of any other Cas9 endonuclease comprising an N-terminal, any fragment of any other Cas9 endonuclease comprising a C-terminal, any fragment of any other intein comprising an N-terminal, any fragment of any other intein comprising a C-terminal is lacking.
Finally, Applicant have not pointed out where in the specification extensive guidance on component selection and functional design such as fragmentation site selection criteria, intein mechanisms could be found. In [70-72], the generic mechanism for intein ligation. This does not provide any guidance regarding fragmentation site selection criteria in either the specific SpCas9 and specific inteins or the broadly claimed Cas9 or inteins. Although this generic knowledge about intein-based ligation is known in the art, split sites in inteins based on this information cannot be predicted. As noted in the rejection, Sun attempted to identify new split sites in a contiguous SspDnaB intein finding 4 out of 13 sites tested that did allow for ligation but could not identify any structural feature that predictable produced fragments capable of ligation (Figure 2). To this end, Sun notes that “Not all split sites in a loop region produced trans- splicing activity, indicating that some loop sequences cannot be broken, possibly because they are required to hold the flanking b-strands in correct conformation” (pgs 35284-35285, bridging para). Therefore, considering a lack of identifying features for a split site in an intein, sufficient disclosure of structures of inteins amenable to fragmentation and sites within the broadly claimed genera of inteins that are amenable to fragmentation are required for a skilled artisan to envision the structures of the fragments of inteins capable of functionally ligating the endonuclease fragments, as claimed.
No fragmentation site selection criteria has been disclosed in the specification. The only fragments of SpCas9 disclosed were known in the art. These were first disclosed by Truong who stresses the identification of just these two sites required careful consideration and thus a skilled artisan cannot easily replace these with any other split site.
Applicant argue that the recited functional limitations for the claimed Cas9 and inteins “limit the claimed scope to functional species.”, again pointing to Example 1 which Applicant allege “provides design principles enabling identification of suitable variants” (page 15, last para). Applicant also allege that “The specification discloses multiple species, validates them experimentally, and explains the functional requirements” (page 15-16, bridging para) pointing to SEQ ID No 1-14, 23-28 (page 16, para 2).
In response, as noted above, disclosure of example 1 is insufficient to provide support to the broadly claimed genera. There are no “design principle” disclosed in example 1.
SEQ ID NO. 1, 6-8, 23-28, are not fragments and thus not relevant to instant written description rejection.
SEQ ID NO: 2, 4 and 3, 5 are fragments of SpCas9 split at residue 573 or 637, as taught by Troung being sites that had to be carefully chosen and tested. However, the claims are not limited to these fragments of SpCas9 but embrace any fragment of SpCas9 comprising an N-terminal and any fragment of any SpCas9 comprising a C-terminal. Critically, the claims also embrace any fragment of any other Cas9 comprising an N-terminal and any fragment of any other Cas9 comprising a C-terminal.
SEQ ID NO. 9, 12 are well-known fragment of Npu intein. SEQ ID NO. 10, 13 are well-known fragment of NrdJ-1 intein. SEQ ID NO. 11, 14 are well-known fragment of Gp41-1 intein. However, the claims are not limited to these fragments of these inteins but embrace any other fragment of these inteins comprising an N-terminal or a C-terminal. Critically, the claims also embrace any fragment of any other intein comprising an N-terminal or a C-terminal.
Finally, claiming structures using functional language does not limit the structures if insufficient disclosure is provided regarding the structures that perform the claimed function. For example, the claim requiring that the Cas9 fragments together form a functional Cas9 is not supported by the specification that does not teach the varied fragments embraces that are capable of combing together to form a whole Cas9.
Applicant's arguments filed 1/26/2026 regarding the U.S.C. 112a – Scope of Enablement rejection of Claims 1-3. 5, 6, 8, 11, 13, 16, 17, 20, 22, 24-26, and 28 have been fully considered but they are not persuasive.
Applicants do not present separate arguments for the U.S.C. 112a – Written Description rejection and the U.S.C. 112a – Scope of Enablement rejection. Attempt is made to properly identify each argument pertinent to the U.S.C. 112a – Scope of Enablement rejection and is addressed below.
Applicant argue that “when the functional and structural limitations of claim 1 as amended are properly considered, Claim 1 defines a method that is commensurate with the specification's disclosure when all of the features are read together. A person of ordinary skill in gene therapy (e.g., holding a PhD and experience with CRISPR/AAV systems) would possess the background knowledge required to practice the claimed method using the specification's guidance combined with routine techniques at least for split Cas9-intein systems, viral vector gene therapy approaches, and CRISPR-mediated exon editing. Practice of these features of claimed invention are performed using techniques known to the skilled person and thus do not require undue experimentation, especially when performed according to the disclosed guidance in the specification.” (page 15, para 3)
In response, as noted in the Scope of enablement rejection above, the claimed method embraces a scope that is significantly broader than the enabled scope. The rejection also establishes the sources of unpredictability in the art such that even a skilled artisan would have to perform undue experimentation to practice the claimed method to its full scope. Milone taught that lentiviral vector use for in vivo gene therapy is currently not feasible and requires more surface engineering experimentation to even start to be able to use this vector system to deliver gene therapy. Mingozzi and Issa taught for AAV vectors route of administration and serotype impact target tissue and transgene expression but not predictably such that any route of administration and serotype could be used to target any tissue and expect therapeutically optimal transgene expression.
Applicant argue that “Claim 1 requires endonucleases and inteins with specific functional requirements: fragmentation, ligation, and also capable of excising target sequences to produce functional dystrophin in the target cells. These functional requirements inherently limit the claimed scope to functional species. The functional aspect is shown in, e.g., Example 1, which provides design principles enabling identification of suitable variants.” (page 15, last para). Additionally, Applicant argue that “Applicant submits that the relevant patent law does not demand that a specification enable every conceivable variation if it provides sufficient guidance for a particular genus.[…] Applicant has disclosed a breakthrough gene therapy approach for DMD, validated it in clinically relevant large animal models and human patient cells, and provided complete enabling disclosure. The claims, properly construed, are thus fully supported. Applicant thus considers that to restrict the claims to only the precise sequences, serotypes, and parameters demonstrated in Example 1 is not legally required and would severely compromise the commercial value of the resulting patent.” (page 16, para 3)
In response, as noted in the response to the written description rejection above, the method disclosed in Example 1 is limited to SpCas9 fragments of SEQ ID NO. 2, 4 and Npu intein fragments of SEQ ID NO. 9, 12. This does not enable the claimed method to its full scope. Furthermore, insufficient guidance is provided regarding the broadly claimed genus and enablement of only the limited scope within the broadly claimed genus does not enable the entire scope. The enabled scope presented above is broader than what is taught in claim 1 which is limited to only intramuscular or intravascular administration of AAV9 with SpCas9 fragments of SEQ ID NO. 2, 4 and Npu split intein fragments of SEQ ID NO. 9, 12.
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 1, 2, 3, 5, 6, 8, 11, 16, 17, 20, 22, 24, 25, 26 over Mali have been considered but are moot because the new ground of rejection necessitated by claim amendment.
Arguments pertinent to instant U.S.C. 103 rejection of claim(s) 1, 2, 3, 5, 6, 8, 11, 16, 17, 20, 22, 24, 25 are addressed below.
Applicant argue that Mali does not teach dendrimer coating for enhanced muscle transduction (page 17). Applicant argue that Mali teaches other vector modifications, such as lipofectamine-based coating which Applicant allege serves the function of immune shielding (page 18, para 1-3). Applicant argue that their dendrimer coating is for a different function i.e. for enhancing cardiac and skeletal muscle transduction (page 18, para 3).
In response, the newly added limitation to claim 1 regarding dendrimer coating of viral vectors is taught by Vetter in the instant rejection. Vetter and Abedi teach the immune shielding properties of dendrimer coating. Thus, both dendrimer coating and lipofectamine coating are recognized to perform the same function. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant argue that Mali does not teach the claimed dual gRNA arrangement within a dual vector system (page 19). Applicant allege that “The gRNA of Mali therefore seems to be exclusively located on the second vector only” (page 19, para 2) and Mali’s teachings regarding gRNA rearrangement is generic such that it “cannot constitute an enabling disclosure of a specific structural arrangement” (page 19, para 3).
In response, rearrangement of nucleic acid sequences in viral vectors is strongly enabled in the art thus a more specific teaching from Mali is not required. Mali acknowledges the space limitation of vectors that may require rearrangement of effector elements. Mali itself teaches several arrangements of effector elements. For example, see Figure 5 that is illustrating a dual AAV system with sgRNAs on both AAVs, a SaCas9 – known for its shorter size- on one AAV and a KRAS effector on another. See Figure 21 with a gRNA on one AAV vector, split Cas9 fragments on two AAV vectors and additional activator/repressor elements on either of the two vectors. See Figure 34 with two different gRNAs on separate AAV vectors, split Cas9 fragments on the two separate AAV vectors, then a repressor on one vector and an activator on another. Thus, arranging the two gRNAs taught by Mali on one or two separate vectors is sufficiently enabled.
Applicant argue that application of In re Japsike is inapposite and allege that “the specific arrangement of gRNAs” represent “represent functionally distinct approaches with different practical consequences” (page 19-20, bridging para). In support, Applicant point to “potential vector packaging constraints” (page 20, para 1), “single-vector delivery of both gRNAs, which would not impose co-transduction requirements” (page 20, para 2), “Single-vector delivery of both gRNAs does not provide” temporal or dose-dependent control over editing efficiency.” (page 20, para 3), “an inherent safety mechanism whereby functional Cas9 nuclease is reconstituted only in cells transduced by both vectors.” (page 20, last para)
In response, Mali acknowledges the well-known packaging size issue with AAV. An ordinary artisan could arrange the gRNA expressing elements on the same or different AAVs to overcome this constraint. However, both scenarios would result in the same functional outcome i.e. expression of the two gRNAs. Same as the claim, Mali’s system also has a co-transduction requirement because a functional Cas9 could only be produced when the cell is transduced with both vectors since the Cas9 is split over the two vectors. Arrangement of the gRNA expressing elements have no impact on the co-transduction requirement. Similarly, since Mali also uses a dual AAV system, temporal or dose-dependent control by adjusting the ratio of vectors administered or the timing of vector administration can be performed. Finally, since Mali also teaches a dual AAV system with split Cas9, the alleged safety mechanism is inherent to Mali as well. Taken together, application on In re Japsike in the instant case is appropriate because arrangement of gRNAs on the same or different vectors would not modify the operation or function of Mali’s or claimed method.
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 13 over Mali, Abedi and Vetter have been considered but are moot because the new ground of rejection necessitated by claim amendment.
Arguments pertinent to instant U.S.C. 103 rejection of claim(s) 13 are addressed below.
Applicant argue that Abedi does not teach coating viral vectors with dendrimers (page 22) and “comparative statement regarding comparative immunogenicity does not constitute a
teaching that AAV vectors should be coated with PAMAM dendrimers” (page 22, para 4)
In response, Abedi is relied upon for its teaching that AAV vectors are known to induce immunogenic response and not for teaching pertaining to coating of viral vectors with dendrimers to reduce their immunogenic response, which is provided by Vetter.
Applicant argue that “Vetter Teaches Dendrimer Coating of Adenovirus, Not AAV-A Fundamentally Different Viral Platform” (page 22). Applicant allege that “The chemical accessibility, surface charge properties, and structural features that make dendrimer coating effective for adenovirus are absent in AAV and lentiviruses” (page 22, para 1).
In response, Applicant provide no evidence that structural features that make dendrimer coating effective for adenovirus are absent in AAV and lentiviruses. Ordinary artisan already applied polymeric coating that were for adenovirus to AAVs. See for example Carlisle et al (J Gene Med 2008; 10: 400–411.) applying HPMA and PEI coatings to AAV5 and AAV8 to reduce their immunogenicity which were first used in adenovirus to reduce their immunogenicity (Abstract). In fact, Applicant also use the method of Vetter without any modifications to their AAVs stating “A person skilled in the art is aware how to coat a vector with a dendrimer coating. An exemplary method is disclosed in Vetter et al.” [0085]. Furthermore, in arguendo, if the structures of adenoviruses are so different from AAVs and lentiviruses that teachings regarding dendrimers could not be applied then it must be noted that specific teachings regarding dendrimer coating of lentiviruses are wholly missing from the specification.
Applicant argue that “Vetter's work specifically addresses adenoviral immunogenicity, which is a characteristic problem of adenovirus but not AAV or lentivirus. AAV vectors are naturally low immunogenicity vectors, having been derived from a non-pathogenic virus.” (page 23, para 2).
In response, immunogenicity of AAVs is known. Abedi provides the requisite teaching. See also Carlisle above. Of note, immunogenicity and pathogenicity are different characteristics such that non-pathogenic elements are still immunogenic.
Applicant argue that “Vetter provides no teaching, suggestion, or guidance regarding application of dendrimer coating to AAV or lentiviral vectors. The teachings regarding adenoviral protein engineering would not predictably transfer to the entirely different structural and immunological context of the claimed viral vectors.” (page 23, para 3).
In response, Applicant fail to provide evidence regarding “teachings regarding adenoviral protein engineering would not predictably transfer to the entirely different structural and immunological context of the claimed viral vectors”. As noted above, from at least Carlisle, ordinary artisan already applied polymeric coating that were for adenovirus to AAVs. Vetter provides the method to apply PAMAM to viral vectors which can be applied to AAVs.
Applicant argue that “Mali teaches away from the Proposed Combination” (page 23) because “Mali explicitly validates an immune-shielding strategy using lipofectamine coating” (page 23, para 4).
In response, teaching of a lipofectamine coating does not teach away from any alternative because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed. See MPEP 2143.01(I)
Applicant allege hindsight reasoning stating “The Examiner provides no explanation for why a skilled artisan would abandon Mali's validated lipofectamine coating approach in favor of an untested, unpredictable combination of references” (page 24, para 1).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, there is no evidence that dendrimer coating of AAVs is unpredictable. Lipofectamine coating of adenoviruses was also known in the art. See abstract in Byk et al (Human gene therapy, 9:2493-2502 (November 20, 1998)). Yet, Vetter used an alternative dendrimer based coating. Using alternative coatings is not an abandonment of Mali’s teachings. Vetter and Abedi provide teachings and motivation to an artisan to use dendrimer based coating for AAVs.
Applicant argue unexpected results with dendrimer coating pointing to Figure 7 and 1 (page 24, para 2, 3). Applicant allege that these results are unexpected because Mali teaches lipofectamine coating for immune shielding and not tropism enhancement thus allegedly teaching away from tropism modification, Vetter teaches dendrimer coating for adenoviruses and provided no teaching regarding enhancing tropism and Abedi provides no teaching regarding enhancing tropism (page 24, para 4). Applicant argue that a skilled artisan has “no reason to expect that dendrimer coating would enhance cardiac transduction in AAV vectors. Rather, the dendrimer coating might instead predictably reduce transduction (through masking of capsid epitopes required for cellular uptake), ablate vector function, or redirect tropism away from cardiac tissue. Under the unpredictability framework discussed above, the outcome of dendrimer coating is not predictable.” (page 25, para 1). Finally, Applicant argue that “Applicant's specification demonstrates not only unexpected enhanced transduction, but unexpected functional cardiac rescue in a large animal DMD model, the first such demonstration in the literature” pointing to Figure 3 (page 25, para 2, 3).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., enhanced tropism) are not recited in the rejected claim(s). 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).
Mali uses AAV8 vector which based on evidence from Zincarelli are known to transduce cardiac and muscle cells, as required by the claim. This property of AAV8 was known. See also Nelson (ref of record) that uses a dual gRNA approach to target exon 23 of dystrophin gene and uses AAV8 because it is “a vector for delivery and expression of the components of the CRISPR-Cas9 system to skeletal and cardiac muscle” (page 405, col. 2, para1) and shows the cardiac tropism in Figure 4 when AAV was delivered systemically, same as Mali.
Further, it is unclear how teachings from Mali, Vetter and Abedi as noted by the Applicant make the instant results unexpected. These teachings do not establish that a skilled artisan expected dendrimer coating to NOT effect tropism such that the effect of dendrimer coating on tropism is unexpected. Applicant provide no evidence that a skilled artisan expects “dendrimer coating might instead predictably reduce transduction (through masking of capsid epitopes required for cellular uptake), ablate vector function, or redirect tropism away from cardiac tissue.”.
Regarding enhanced tropism in Figure 7, a nexus between result of Figure 7 and the instant claims is not established. Figure 7 uses a specific coating, PAMAM, on a specific AAV, AAV9, which delivers a Cre transgene. “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range” MPEP 716.02(d). Herein, Applicant provide no evidence that the result of Figure 7 occurs over the entire claimed genera of any dendrimer, any AAV serotype. Furthermore, the specification does not compare non-PAMAM coated AAV9s with PAMAM-coated AAV9 in Figure 1 or 3. For human tissue, a non-PAMAM coated AAV6 is shown as result effective (Figure 4). In Figure 6c, the specification shoes some editing efficiency of intravenous PAMAM-coated AAV9 in the heart but it cannot be established this result could be of any statistical and practical significance in comparison to Mali. MPEP 716.02(b) states that The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." The relevance of these data to Mali is not clearly established since Mali teaches AAV8 that inherently transduces both skeletal muscle and the heart when injected intravenously. Nelson using intravenous AAV8 to deliver CRISPR reagents to target dystrophin gene, same as Mali, shows the cardiac tropism and recovery of dystrophin protein in Figure 4. Additionally, the claim is not limited any specific means of administration such an artisan could use direct tissue administration to transduce desired cell types. Finally, “Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention” (MPEP 716.02(c). Herein, on balance, the results presented lack sufficient nexus with the claimed invention and Applicant fail to establish that the results are unexpected with both statistical and practical significance. On the other hand, the prior art provided sufficient teaching, suggestion and motivation to use dendrimer coating for viral vectors such as AAV.
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 28 over Mali, Amoasii, NG_012232.1 have been considered but are moot because the new ground of rejection necessitated by claim amendment.
Arguments pertinent to instant U.S.C. 103 rejection of claim(s) 28 are addressed below.
Applicant argue that “Mali and Amoasii Teach Fundamentally Different Mechanisms” (page 26) alleging that Mali’s Figure 23 only shows dual-gRNA flanking deletion of exon 23 while Amoassi shows single gRNA (page 26, para 3, 4).
In response, Mali teaches both a single and a dual gRNA approach in Figure 23 as alternatives.
Applicant allege hindsight reasoning because “The fact that Mali teaches both single-gRNA and dual-gRNA approaches does not provide motivation to substitute Mali's approach into Amoasii's exon 51 context. Rather, it merely reflects that Mali discusses multiple approaches without teaching or suggesting that they are interchangeable between different exon targets or different disease contexts” (page 26, last para).
In response, Mali presents the single and dual gRNA approaches to perform the same function of rescuing the dystrophin expression [0057]. Both approaches target the same mutated exon, however Mali shows that the dual gRNA approach has better results thus motivating an artisan to use the dual gRNA approach (Figure 23).
Applicant argue that “Claim 28 is patentable over Mali because Mali explicitly teaches exon 23 deletion targeting (FIG 23, 0028, 0057) and makes no disclosure of exon 51 as a target
sequence for dystrophin genome engineering” and “The specific gRNA sequences claimed in Claim 28 (SEQ ID NOs: 25-28) are uniquely designed to target the sequences flanking exon 51 and were not suggested by Mali's disclosure.” (page 27, para 1).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Exon 51 is taught by Amoasii. gRNA sequences of claim 28 are not required and merely alternative to option (i). Mali teaches gRNA designs and makes many gRNAs for different target sequences. An ordinary artisan can design gRNAs to target exon 51 since this sequence was known and taught by NG_012232.1.
Applicant argue unexpected results stating “While exon skipping as a general therapeutic principle is known in the art, the specific implementation of exon 51 deletion using the dual-vector, dual-gRNA architecture with enhanced muscle transduction via dendrimer coating demonstrates technical unpredictability in gRNA design and represents a non-obvious combination of known elements to achieve a particular clinical outcome. Mali teaches neither exon 51 deletion nor any suggestion to combine its split-Cas9 system with this specific exon-targeted application” (page 27, para 2).
In response, Exon 51 is taught by Amoasii not Mali in the rejection. Applicant provide no evidence for their allegation of unpredictability or provide any support for unexpected results. previous arguments for unpredictability and unexpected results were unpersuasive.
Applicants argue “No Motivation to Modify Amoasii's Validated Single-gRNA Approach with Mali's Dual-gRNA Strategy” (page 27) because Amoasii validates their sgRNA approach and allege that combination of Mali and Amoasii would require a number of workovers (page 27, last para). Applicant argue hindsight reconstruction stating that “The Examiner provides no motivation found in the prior art for modifying Amoasii's validated approach.” (page 27-28, bridging para).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Furthermore, there is no requirement that the motivation must be found in the prior art. MPEP 2143 states “The courts have made clear that the teaching, suggestion, or motivation test is flexible and an explicit suggestion to combine the prior art is not necessary. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. Id. at 1366, 80 USPQ2d at 1649. "[A]n implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the ‘improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves. In such situations, the proper question is whether the ordinary artisan possesses knowledge and skills rendering him capable of combining the prior art references." Id. at 1368, 80 USPQ2d at 1651.
Finally, Mali provides the requisite motivation showing the dual gRNA approach is better than the single gRNA approach.
Conclusion
No claim is allowed.
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 MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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