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 the invention of Group I, claims 1-38 and 47 drawn to a modified oligonucleotide with a modified internucleoside linkage wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of a PMP22 RNA, and a pharmaceutical composition, in the reply filed on 1 November 2024 was previously acknowledged. The restriction requirement is therefore made final.
Election of Species
The requirement for election of a single species from each species group A - E was also previously removed.
Amendment and Status of Claims
This action is in response to papers filed 25th Jul 2025, in which claims 2-4, 14, 32, and 33 were amended, claim 13 was canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
Applicant has amended:
claim 33 to overcome the 112(b) rejections; the previous 112(b) rejections of claim 33 are withdrawn.
Applicant’s arguments, see Pgs. 7 onwards, filed 25th Jul 2025, with respect to:
rejections of claims under 35 USC § 103 have been fully considered and are persuasive for the reasons discussed in this office action. The 35 USC § 103 rejections are withdrawn.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Objections and Rejections not reiterated here are withdrawn.
Claims 2-38 and 47 are under consideration. This Office Action includes rejections not necessitated by amendment.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-38 and 47 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 claims contain 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.
MPEP 2163.II.A3.(a).(i) states the following:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by I. 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 II. functional characteristics coupled with a known or disclosed correlation between function and structure, or by III. a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.”
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Written Description Rejection
Claims 2 and 3 recite “a modified oligonucleotide consisting of 12 to 50 linked nucleosides …wherein the modified oligonucleotide has: a 5'-region consisting of 1-5 linked 5'-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3'-region consisting of 1-5 linked 3'-region nucleosides”; and also recite having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, or 16 contiguous nucleobases of any of SEQ ID NOS: 2348, 3078, and 3807 (claim 2) or a sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of: an equal length portion of nucleobases 12,357-12,387 of SEQ ID NO: 2 (claim 3). Nucleobases 12,357-12,387 of SEQ ID NO: 2 are 30 nucleotides in length and encompass SEQ ID NOS: 2348, 3078, and 3807, which are each 16 nucleobases.
Claim 4 recites “The oligomeric compound of claim 3, wherein the modified oligonucleotide has a nucleobase sequence that is at least 80%, 85%, 90%, 95%, or 100% complementary to any of the nucleobase sequences of SEQ ID NO: 2.”.
Claim 22 recites “The oligomeric compound of claim 3, wherein the modified oligonucleotide consists of 12-30, 12-22, 12-20, 14-18, 14-20, 15-17, 15-25, 16-20, 18-22 or 18-20 linked nucleosides.”.
Species Encompassed and Disclosed in the Specification
i. The # of nucleobases: Regarding claims 2 and 3, the modified oligonucleotide recited consists of 12 to 50 linked nucleosides encompassing SEQ ID NOS: 2348, 3078, and 3807.
SEQ ID NOS: 2348, 3078, and 3807 are described in the specification.
See Pg. 133:
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And Pg. 47:
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Further, various base and sugar modifications on it are described.
ii. The gapmer design of nucleobases: Regarding claims 2 and 3, the modified oligonucleotide recited consists of the following gapmer 5’-(1-5)-(6-10)-(1-5)-3’ design.
However, the specification describes only: 3-10-3 cEt gapmers. See Table 1 on pg. 55.
iii. The % identity of nucleobases:
Regarding claim 4, the modified oligonucleotide recited consists of 12 to 50 linked nucleosides encompassing nucleobases 12,357 – 12,387 of SEQ ID NO: 2 (30 nucleotides in length). A sequence that consists of at least 80% complementarity to 50 nucleotides of SEQ ID NO: 2 includes a large genus of sequences comprising nucleotide sequences that may be ≤20% different from SEQ ID NO: 2; i.e., 10 nucleotides could be different. Furthermore, a nucleotide sequence could be or have:
up to 20% of the nucleotides removed from SEQ ID NO: 2;
a single chunk comprising ≤20% of the nucleotides different from SEQ ID NO: 2;
every 5th nucleotide (starting at any position) different from nucleobases SEQ ID NO: 2;
every 5th nucleotide (starting at any position) removed from SEQ ID NO: 2;
any other combination of nucleotides mutated or removed as long as the total adds up to ≤20% of total nucleotides.
However, only sequences with 100% complementary identity to nucleobases 12,357 – 12,387 of SEQ ID NO: 2 are described.
Similar considerations can be made for the remaining % identities recited in claim 4 and claim 22.
iv. The # of linked of nucleosides:
The claims recite “The oligomeric compound of claim 3, wherein the modified oligonucleotide consists of 12-30, 12-22, 12-20, 14-18, 14-20, 15-17, 15-25, 16-20, 18-22 or 18-20 linked nucleosides.” And the specification repeats:
Embodiment 22. The oligomeric compound of any of embodiments 1-21, wherein the modified oligonucleotide consists of 12-30, 12-22, 12-20, 14-18, 14-20, 15-17, 15-25, 16-20, 18-22 or 18-20 linked nucleosides. See pg. 11, lines 14 – 16. There is no other disclosure of linked nucleosides.
Each of those categories (i – iv) described above comprises a broad subgenus with diverse members and different structures that affect their functions. Some of those structures may have altered mRNA binding, to include off-target binding and thus toxicity.
Although the specification discloses what the elements of oligonucleotides complementary to SEQ ID NO 2 as claimed are intended for; compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PMP22 RNA in a cell or animal, and in certain instances reducing the amount of PMP22 protein in a cell or animal (first line of Field of Invention, pg. 1); it does not teach any core structure that is responsible for the intended function of the modified oligonucleotide. For e.g., it does not teach which 20% of nucleotides may or may not be altered for the modified oligonucleotide to function. It does not teach which 80% of nucleotides must be present or must not be altered for the modified oligonucleotide to function. It does not teach the portion of the sequence necessary to carry out those functions. Although the specification teaches what nucleobases a modified oligonucleotide consisting of 12 to 50 linked nucleosides of SEQ ID NO: 2 is in terms of their functional characteristic, the functional characteristic is not coupled with a known structure.
The specification has not adequately described the genus of sequences for these reasons.
With respect to the gapmer design of nucleobases recited in claims 2 and 3, the BRI of the claims that require the following gapmer 5’-(1-5)-(6-10)-(1-5)-3’ design is that gapmer can be a minimum of 8 nucleobases to a maximum of 20 nucleobases; i.e., the recited gapmers range from 50% smaller to 50% bigger than the disclosed gapmers. However, the specification describes only: 3-10-3 cEt gapmers. See Table 1 on pg. 55. A 3-10-3 gapmer is 16 nucleobases in length. One of skill in the art wouldn’t readily know how to alter the nucleobases to this significant (50%) difference and yet achieve the intended function.
Because the specification does not describe the locations and % of the modified oligonucleotide that may be altered within nucleobases 12,357 – 12,387 of SEQ ID NO: 2, there is no guidance for the skilled artisan to prepare a modified oligonucleotide with less than 100% identity to nucleobases 12,357 – 12,387 of SEQ ID NO: 2 that retains the claimed function; i.e., inhibit PMP22 mRNA. It is not predictable based on the species disclosed in the specification, or the level of guidance provided in the specification, that a skilled artisan could prepare an insert with less than 100% identity to nucleobases 12,357 – 12,387 of SEQ ID NO: 2 and retain the claimed function.
In summary, the specification describes three species within the claimed genus – a sequence consisting of SEQ ID NO: 2348, 3078, and 3807. The specification does not provide predictability for sequences I) with less than 100% identity to these recited sequences and II) which target PMP22 mRNA.
Guidance Provided by the Art
Gapmer Design, previously cited, teaches that complementarity to a target isn’t sufficient in designing an ASO. Data from a screen using a set of 21 ASOs targeting a single mRNA in mouse kidney identified (only) four (4) active ASOs.
Thus, the art doesn’t teach how an optimized 3-10-3 gapmer may be modified to a, for e.g., 5-10-5 gapmer to achieve the same (high) efficiency of reducing the amount /activity of an mRNA.
Dependent Claims
Claims 5-38 and 47 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.
Therefore, these claims are also rejected.
Conclusion of Written Description Rejection
While none of the above elements are specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of an invention of “a modified oligonucleotide consisting of 12 to 50 linked nucleosides …wherein the modified oligonucleotide has: a 5'-region consisting of 1-5 linked 5'-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3'-region consisting of 1-5 linked 3'-region nucleosides” (claims 2 and 3); having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, or 16 contiguous nucleobases of any of SEQ ID NOs: 2348, 3078, and 3807 (claim 2) or a sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of: an equal length portion of nucleobases 12,357-12,387 of SEQ ID NO: 2 (claim 3); or modified oligonucleotide that …has …80%... of SEQ ID NO: 2 (claim 4); or “the modified oligonucleotide that consists of 12-30, 12-22, 12-20, 14-18, 14-20, 15-17, 15-25, 16-20, 18-22 or 18-20 linked nucleosides.” (claim 22).
Therefore, claims 2-4 and 22 are rejected for lack of written description. Claims 5 – 21, 23 – 38, and 47 are rejected because they depend on Claim 3 and do not remedy the issues.
Withdrawn Claim Rejections - 35 USC § 103
Response to Arguments
Applicant's arguments filed 25th Jul, 2025 to a prima facie case of obviousness of claim rejections under 35 USC § 103 have been fully considered and are persuasive. Indeed, nothing in the applied reference of Zhou would have motivated one of ordinary skill in the art to specifically select SEQ ID NO: 92938 out of the 997,516 sequences disclosed in Zhou, and then modify it in order to arrive at a compound comprising a modified oligonucleotide as presently claimed. Therefore, the 35 USC § 103 rejection in view of Zhou and Khvorova has been withdrawn.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11136577. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the patent anticipate the claims of the instant invention. The instant claim 40 is more broadly drawn to treating diseases associated with PMP22, with an oligomer as recited in instant claims 2-38 and 47, while the patent is more limited to treating CMT which is associated with PMP22 and where the instant claims are also drawn to treating CMT (see claims 162-163, for example).
Any additional limitations of the ‘577 claims are encompassed by the open claim language “comprises” found in the instant claims.
Claims 2-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 138-167 of U.S. Patent No.11959080. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant invention are obvious in view of the claims of the patent. Withdrawn claims 40-46 of instant application are more broadly drawn to treating diseases associated with PMP22, with an oligomer as recited in instant claims 2-38 and 47, while the patent is more limited to treating CMT which is associated with PMP22, and where the instant claims are also drawn to treating CMT (see claims 42-44, for example). The composition used in the treatment as recited in reference application; i.e. SEQ ID Nos: 9-16 are complementary to SEQ ID NO: 2 of instant application. For e.g., alignment of SEQ ID NO: 16 of reference app. with SEQ ID NO: 2 shown below:
16_17493112/c
Query Match 0.0%; Score 16; DB 1; Length 16;
Best Local Similarity 100.0%;
Matches 16; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 37227 GCTGTTGATTGAAGAT 37242
||||||||||||||||
Db 16 GCTGTTGATTGAAGAT 1
Any additional limitations of the ‘080 claims are encompassed by the open claim language “comprises” found in the instant claims.
Claims 2-47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 138-159 of U.S. application No. 18/599,942. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the patent anticipate the claims of the instant invention. The instant claims 2-47 are more broadly drawn to treating diseases associated with PMP22, with an oligomer as recited in instant claims 2-38 and 47, while the reference application is more limited to treating CMT which is associated with PMP22 and where the instant claims are also drawn to treating CMT (see instant claims 42-44, for example). Reference claim 138 also has a step of determining if and individual shows slowed motor nerve conduction velocity (MNCV) and/or reduced compound muscle action potential (CMAP). Since slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potential (CMAP) are associated with CMT it would have been obvious to test for such symptoms.
Any additional limitations of the ‘942 claims are encompassed by the open claim language “comprises” found in the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Remarks:
2. Applicant's arguments filed 07/25/2025 have been fully considered but they are not persuasive because applicant did not address the merits of the provisional rejection.
It is noted the response states that they will address the rejection at such time as the claims are otherwise considered allowable.
Subject Matter Free of the Prior Art
The sequences bearing SEQ ID NOs: 2348, 3078, and 3807 recited in claim 2 are free of the art of record.
Conclusion
No claims are allowed.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached on (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SHABANA S MEYERING/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635