DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-11 and 16 drawn to a nucleic acid regulatory element (NRE) for enhancing muscle-specific gene expression) in the reply filed on 2nd September, 2025, was previously acknowledged. Additionally, Applicant’s election without traverse of the promoter spC5-12 for species in the same reply was also previously acknowledged.
Claims 13 - 15 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2nd Sept, 2025.
Priority
A certified English language translation of priority document EP 20158064.4 has been properly added to the priority chain. The copy has been made available from the WIPO Digital Access Service. The certified copy provides support for the priority date to be the filing date of the foreign application; i.e., Feb 18th, 2020.
Acknowledgement is also made of Applicant’s National Stage entry of PCT Application
PCT/EP2021/053939 filed on Feb 18th, 2021 and corresponding oath.
Amendments
This action is in response to papers filed 21st Jan 2026, in which claims 1, 5, and 10 were amended, no claims were canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
Applicant has amended:
Abstract, specification, and drawings to overcome objections; the previous objections are withdrawn.
claim 5 to overcome the 112(b) rejections; the 112(b) rejections of claim 5 is withdrawn.
claims 1 and 10 to overcome the 112(a) rejection; the 112(a) rejection is not withdrawn.
claims 1 and 10 to overcome the NSDP rejections of claims; the NSDP rejection is withdrawn.
Applicant’s arguments, see Pgs. 11 - 13, filed 21st Jan 2026, with respect to:
rejections of claims 1-11 and 16 under 35 USC § 103 have been fully considered and are persuasive for the reasons discussed in this office action. The 35 USC § 103 rejection is withdrawn.
Arguments applicable to amended claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Oath/Declaration
The declaration filed 21st Jan 2026 is entered. The declaration demonstrating unexpected results is persuasive.
The Declaration shows, in heart tissue, the elements Csk-SH1 in combination with Dph-CRE02 provides for enhanced gene expression over the prior art the combinations of either Csk-SH4 or Csk-SH4 in combination with Dph-CRE02. Evidence in the prior art indicated that a similar expression of Csk-SH1-CRE02 to Csk-SH4-CRE02 and Csk-SH5-CRE02 might be seen. Therefore, evidence of increased expression driven by instantly claimed Csk-SH1-CRE02 over SH4-CRE02 and SH5-CRE02 was not expected.
However, it is noted that the evidence in the Dec is with full length SH1 (SEQ ID NO: 2) and not a “functional fragment thereof”.
Status of Claims
Claims 1-11 and 16 are currently under consideration.
Claim Rejections - 35 USC § 112
This rejection retains only a portion of the rejection from Non-final Office Action of 10/01/2025 that is directed to unamended limitations, specifically functional fragment of SEQ ID NO: 2.
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 1-11 and 16 remain 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, as set forth in the non-final office action of 10/01/2025.
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.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997).
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, 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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
Scope of the Invention
In the instant case, the genera are
A muscle-specific regulatory element comprising a sequence defined by SEQ ID NO: 2 or functional fragments thereof (recited in claim 1 and 10).
A combination of #1 above along with a known promoter e.g., Spc5-12 (the elected species) (claims 2-11 and 16).
The broadest reasonable interpretation (BRI) of the scope of the genera listed above is a hybrid promoter made up of a diaphragm-specific enhancer and a muscle-specific regulatory element that drives expression of a transgene in the muscle. This interpretation is based on definitions on pg. 15: "diaphragm-specific enhancer" is an enhancer that preferentially drives expression of a gene operably linked to said transcription regulatory element in the diaphragm AND when present in a hybrid promoter with a muscle-specific regulatory element, drives expression of a gene operably linked to it in the muscle. Thus, such a hybrid promoter is suitable for gene therapy of muscular and neuromuscular diseases (pg. 1 and 34).
Disclosure of a Complete or Partial Structure
Regarding 1) muscle-specific regulatory element, Applicant describes muscle-specific regulatory element(s) to be preferentially SEQ ID NO: 2 consisting of 381 bases. Various fragments include: having at least 95% identity to a SEQ ID NO: 2 [pg. 4, Aspect 1]. Functionally, the regulatory element and fragments must have muscle-specific enhancer activity [or a functional fragment, pg. 4, Aspect 1]. The inventive concept requires the enhancer and fragments to retain their ability to drive expression of a gene in the muscle so as to function in gene therapy of neuromuscular diseases [BRI]. Further description includes combining a diaphragm-specific enhancer or combining SEQ ID NO: 1 with a muscle-selective enhancer SEQ ID NO: 2. In any case, the enhancer(s) are combined with a muscle-specific regulatory element to result in a novel regulatory element [pgs. 3-4]. The working examples were discussed in previous office action. However, it is not clear how the functional fragments may be produced; i.e., it is not clear how SEQ ID NO: 2 may be varied so that the fragments retain the functions that define them; i.e., driving muscle-specific transgene expression, as described by the rest of the disclosure.
Regarding 2) the combination of diaphragm -selective enhancer and muscle-specific regulatory element along with a known promoter such as Spc5-12, Applicant describes the combination to be (SEQ ID NO: 1 + SEQ ID NO: 2 = SEQ ID NO: 3) + SEQ ID NO: 4 (Spc5-12). It is not disclosed if SEQ ID NO: 1 and the fragments of SEQ ID NO: 2 as recited are not to be part of the combination; i.e., SEQ ID NO: 3.
Structure/Function Correlation
Applicant’s claims encompasses particular sequences of enhancer and promoter elements with the proviso that they allow for the sequences, working alone or in combination with each other, to enhance transgene expression so as to function in gene therapy of neuromuscular diseases (BRI), while only specific sequences are described in the instant specification without any correlation to what core sequence is encompassed by the recited sequences. The breadth of the claimed genera is enormously broad with an unfathomable number of structurally divergent and diverse sequences.
Regarding all the sequences claimed, Applicant has not demonstrated possession of any sequence that could be called a muscle-specific regulatory element that will enhance transgene expression in the muscle, other than the full-length sequence identified as SEQ ID NO: 2. The examples do not provide support for the entire genus/subgenera of sequences claimed because the examples show only individual species. The Specification does not provide sufficient evidence that each member of the entire genus of sequences claimed would produce the intended outcome of enhance transgene expression in the muscle. The Specification does not provide specific guidance for determining what fragments of sequences should be that will enhance transgene expression in the muscle; the functional characteristic is not coupled with a known structure.
The Spec. does not identify a core structure necessary for being a muscle-specific regulatory element that will enhance transgene expression in the muscle. Among the evidences provided for a muscle-specific regulatory element that will enhance transgene expression in the muscle, no core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for the muscle-specific regulatory element that will enhance transgene expression in the muscle is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing.
Altogether, the number of species (1) disclosed by complete structure is not sufficient to provide the written description support for the huge genus of muscle-specific regulatory elements that will enhance transgene expression in the muscle claimed.
These are broad genera with diverse members and different structures that underly their functions. Although the claims recite compounds that inherently possess a functional characteristic, i.e., enhance transgene expression in the muscle, the functional characteristic is not coupled with a known structure.
Knowledge from the State of the Art
Chuah (Chuah et al., Molecular Therapy, Volume 22, Issue 9, September 2014, Pages 1605-1613), which would be considered the closest prior art teaches cis-acting regulatory modules (CRMs) identified in a genome-wide bio-informatics strategy. This data-mining approach identifies several sequences as a cis-regulatory module (CRMs) with robust regulatory activity and further analyze expression patterns from an AAV construct bearing the CRMs in vivo. Chuah teach that for a CRM to act, the modules within that function as transcription factor binding sites (TFBs) must be preserved. This teaching is derived from computationally determining consensus regions of TFBs within CRMs across species (Fig. 1). While the consensus sites are deemed important, nothing in the art teaches one of skill how to vary the regions within such sites.
Dependent Claims
Claims 2 - 10 and 16 do not further limit the genus of nucleic acid molecules so as to resolve the issues above, and are therefore, not sufficiently described for at least the reasons above.
Conclusion of Written Description
While none of these elements is specifically required to demonstrate possession, in combination their lack means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of an invention of any oligonucleotide sequence of functional fragments of muscle-specific regulatory element, or any combination thereof.
Therefore, the examiner concludes there is insufficient written description support for the instantly claimed genera of muscle-specific regulatory element, and combinations with other enhancers and promoters as stated. Only the entire SEQ ID NO: 2 as the muscle-specific regulatory element but not the full breadth of the claims is supported by Applicant’s disclosure.
Withdrawn Scope of Enablement
Upon reconsideration of the scope of enablement rejection of claims 1-10 and 16 as set forth in the non-final office action of 10/01/2025, this rejection is withdrawn. The written description rejection above sufficiently describes the “missing” description as required by §112a.
Response to Arguments
Applicants arguments presented on 21st Jan 2026 in response to the §112a rejections made in the non-final office action of 10/01/2025 have been fully considered but are unpersuasive. Applicants argue that the amendments made to the claims have overcome the rejection.
Applicants have amended claims to remove the limitation “95% identity”. However the rejection also was directed to functional fragment thereof. Since this limitation has not been amended, the written description rejection under §112a is maintained.
Withdrawn Claim Rejections - 35 USC § 103
The declaration overcomes the §103 rejection of claims 1-10 and 16 as set forth in the non-final office action of 10/01/2025; this rejection is withdrawn.
Response to Arguments
Applicants arguments presented on 21st Jan 2026 in response to the §103 rejections made in the non-final office action of 10/01/2025 have been fully considered and are persuasive.
1. Applicant asserts on pg. 11, second to the last paragraph, “Chuah 2018, alone or in combination with Chuah 2015, does not teach or reasonably suggest the nucleic acid regulatory elements as recited in the amended claims. In particular, the combination of Chuah 2018 and/or Chuah 2015 does not teach or reasonably suggest the elements of the nucleic acid regulatory elements as recited in the amended claims as a single sequence.”.
This is unpersuasive because:
a) Chuah 2018 had taught Dph-CRE02; i.e., instant SEQ ID NO: 1 (Chuah 2018, Table 4, page 29, SEQ ID NO. 2; Example 1 ).
b) CHUAH 2015 had taught cardiac and skeletal muscle-specific regulatory elements for enhancing muscle-specific gene expression. Specifically, CHUAH 2015 taught CSk-SH1; i.e., instant SEQ ID NO: 2 (CHUAH 2015, abstract; Fig. 2, SEQ ID NO: 1; Examples 4 - 7). CHUAH 2015 validate CSk-SH1 in vitro and in vivo experiments to show increased muscle-specific luciferase expression.
The combination of known prior art elements is a rationale to explain obviousness. Thus, instant SEQ ID NO: 3 (combination of instant SEQ ID NO: 1 + instant SEQ ID NO: 2 = instant SEQ ID NO: 3) was taught by the combined art discussed above.
Applicants argument that neither reference teaches the entire sequence i.e., instant SEQ ID NO: 3 is akin to arguing against references individually which is invalid considering that the rejection was made using an obviousness rationale of combining prior art elements.
2. Applicant asserts at page 11-12 of the response the instant application demonstrates unexpected results; the declaration shows “comparative data of the combination of Dph- CRE02 and CSk-SH1 with the combinations of Dph-CRE02 and CSk-SH5 and Dph-CRE02 and Sk-SH4, disclosed in Chuah 2018 demonstrates enhanced luciferase expression from the SpcS-12 promoter by the combination of Dph-CRE02 and CSk-SH1 compared to the combination of Dph- CRE02 and CSk-SH5 and the combination of Dph-CRE02 and Sk-SH4 as disclosed in Chuah 2018.”.
This is persuasive as discussed above and further below:
Briefly, Applicants have i) provided experimental validation of prior art known elements, and ii) the demonstrated results are unexpected when interpreted in view of the prior art. Declaration provides results obtained for Dph-CRE-02 combined with CSk-SH1 in heart tissue.
The known prior art elements are Dph-CRE-02 and CSk-SH1, the individual components of the hybrid regulatory enhancer. Each of these enhancers were taught and individually tested by the prior art. See the prior art analysis below:
Chuah 2018 had taught CSk-SH1 (SEQ ID: 123), pg. 65; diaphragm CREs that are the most robust are: CRE02 (SEQ Id NO: 2, i.e., instant SEQ ID NO: 1). They evidence this conclusion by the following from pg. 67: CRE02 combined with i) the muscle CRE (Sk-SH4) is shown to: augment luciferase expression by 400-600 fold when driven from the human Desmin 1.4kb promoter. Expression result in heart tissue are in Fig. 5h. ii) the CSk-SH5 leading augmentation of about 300 fold luciferase expression when compared to luciferase expression driven from just the SPc5-12-GTRM promoter.
The expression results of various CREs in combination with CSk-SH1 were not shown, possibly not tested.
Instant application requires CSk-SH1, not CSk-SH4. However, the following recitation from pg. 7 of Chuah 2018:
In a preferred embodiment, the skeletal muscle CRE Sk-SH4 (SEQ ID NO: 121), or the skeletal muscle and cardiac CREs CSk-SH5 (SEQ ID NO: 122) and CSk-SH1 (SEQ ID NO: 123) regulatory elements are used in combination with the Dph-CREs.
can reasonably be concluded to mean that equivalent results for all similar combinations are to be expected. See further breakdown of prior art knowledge below:
Chuah 2018 had further made a case for combining regulatory elements. See recitation from pg. 3:
Even more preferably, Dph-CRE64 is used for treating diseases which require upregulation of transgene expression in Diaphragm and skeletal muscle, and less in heart. In a specific embodiment, these Dph-CREs, more preferably the Dph-CRE64 (or Dph-CRE02 or CRE-21) are combined with muscle specific CRE Sk-SH4.
from pg. 66:
In particular, the diaphragm specific CRE (Dph-CRE64, CRE02, and CRE21) coupled
to the muscle specific CRE (Sk-SH4) act synergistically as a combined module, leading to an
35 extremely high level of enhancement of luciferase expression in vivo.
CHUAH 2015 had not taught any combination of CSk-SH with Dph-CRE. However, CHUAH 2015 had taught superiority of individual CSk-SH; e.g., augmentation of 25-fold luciferase expression for CSK-SH1 (instant SEQ ID NO: 2), (middle of pg. 50).
CHUAH 2015 conclude, see recitation from pg. 50: These in vivo data show that the nucleic acid regulatory elements CSk-SH, in particular CSk-SH1 , CSk-SH3 and CSk-SH5, more particularly CSk-SH1 and Csk-SH5, can enhance heart and skeletal muscle-specific luciferase expression.
Thus, Chuah 2018 and CHUAH 2015 imply equivalence of the combination of Dph-CRE-02 with CSk-SH1 with other known and tested combinations.
However, the declaration shows that instantly claimed combination demonstrates unexpectedly superior results. In view of the foregoing, the §103 rejection of claims 1-11 and 16 is withdrawn.
Withdrawn Double Patenting
The rejection of Claims 1-10 and 16 on the ground of nonstatutory double patenting as being unpatentable over i) claims 1-37 of U.S. Patent No. 11920149 (Application No.16-498-690), ii) over its divisional application – US Patent 12571000 (previously 18417465), and iii) claims 1, 6-15 of U.S. Patent No. 12427205 (Application No. 17760333) is withdrawn.
Response to Arguments
Applicants arguments presented on 21st Jan 2026 in response to the double patenting rejections made in the non-final office action of 10/01/2025 have been fully considered but are unpersuasive. Applicants argue that the pending claims are patentably distinct from the claims of the '149 and '205 patents and the '465 application for the same reasons as discussed above; i.e., exceptional results.
This is not persuasive. The evidence of exceptional results does not overcome a double patenting rejection.
However, the rejection is withdrawn on account of amendments.
Conclusion
No claims are 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635