DETAILED ACTION
This Action is in response to the communication filed on 05/29/2025.
Claims 1-14 are pending.
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 species Alkyl group represented by formula (III), and cerebral cortex in the reply filed on 05/29/2025 is acknowledged.
Claim 8 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, as acknowledged in response filed 05/29/2025 there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/29/2025.
Claims 1-7, 9-14 are under consideration.
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 1-7, 9-14 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 for treating a central nervous system disease of a subject by regulating the expression or editing of a target RNA in the central nervous system of the subject, comprising intravenously or subcutaneously administering to the subject a double-stranded nucleic acid agent consisting of a first nucleic acid strand and a second nucleic acid strand, wherein the first nucleic acid strand comprises a base sequence capable of hybridizing with at least part of the target RNA and has an antisense effect on the target RNA; wherein the second nucleic acid strand comprises a base sequence complementary to the first nucleic acid strand and is conjugated to a tocopherol, cholesterol, an analog thereof , or an alkyl group represented by general formula (III): [wherein Rx represents a C6-C12 linear alkylene group], , wherein the first nucleic acid strand is annealed to the second nucleic acid strand, and wherein the subject has a central nervous system disease,
does not reasonably provide enablement for the broadly claimed method where the alkyl group has a substituent and/or wherein Rx represents anything other than a C6(OH)-C12(OH) linear alkylene group. 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 and use the invention commensurate in scope with these claims. Emphasis added for clarity.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988).
Wands states on page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., lnc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). More specifically, the claimed invention is drawn to a method of therapy using an oligonucleotide to inhibit the expression of a target to treat a central nervous system disease in a subject.
The breadth of the claims
The claims are broad with respect to the oligonucleotide that is used in the method. Specifically, the claims explicitly encompass the use of an oligonucleotide wherein the second strand is conjugated to an alkyl group optionally having a substituent; wherein said alkyl group optionally having a substituent is represented by the general formula (III) as indicated in claim 1: [wherein Rx represents a C3-C24 linear alkylene group] (the elected species). As such the claims encompass a method of treatment using an oligonucleotide that is conjugated to an alkyl group that comprises any substituent and wherein Rx represents a C3-C24 linear alkylene group.
The unpredictability of the art and the state of the prior art
The claimed method is drawn to treating a central nervous system disorder in a subject using an oligonucleotide that inhibits expression of a target gene in affected cells of the central nervous system (CNS). The claims encompass intravenous as well as subcutaneous administration of the oligonucleotide which then must travel to the diseased cells of the CNS which requires the oligonucleotide to pass the blood brain barrier (BBB) which plays a role to protect the brain from harmful substances and also acts as a barrier to delivering a drug to the brain. Delivering oligonucleotides across the BBB to treat CNS disorders is problematic as the BBB presents an obstacle to delivery of oligonucleotides to the brain, as acknowledged by the specification (e.g., see paragraph [0006] of the published application (U.S. 20230024153)). Furthermore no prior art has been identified or is cited which demonstrates delivery of an oligonucleotide similar to the oligonucleotide used in the claimed method across the BBB to treat CNS disorders. Therefore, at the time the claimed invention was filed, the state of the art was that treatment of CNS diseases using oligonucleotides which must pass the BBB was highly unpredictable.
Working Examples and Guidance in the Specification
The specification provides a working example demonstrating that double-stranded nucleic acids comprising C6(OH)HDO, C9(OH)HDO, and C12(OH)HDO (see Example 31 starting at [0629] and Figures 58-59). The double-stranded nucleic acids used in Example 31 do not comprise substituents. It is also respectfully pointed out that the specification also discloses an example wherein a double stranded oligonucleotide with docosahexaenoic acid (DHA)-conjugated to the complementary strand was administered to a subject, but results demonstrates that DHA-HDO did not suppress the expression of the target non-coding RNA in any of the cerebral cortex, cerebellum, striatum, hippocampus, and brainstem, compared with the negative control (see Example 19 starting at [0477], especially [0488], and Figures 37-38).
Therefore, the state of the art at the time of filing and the evidence of record and disclosed in the specification indicates that the delivery of oligonucleotides across the BBB is unpredictable and the only evidence of record demonstrating successful delivery of across the BBB into brain cells is the experiment showing that double-stranded nucleic acids comprising C6(OH)HDO, C9(OH)HDO, and C12(OH)HDO (i.e., C6-C9 linear alkylenes without substituents) (See Example 31). Accordingly, the disclosure, in view of the state of the art at the time of filing, only enables the claimed method wherein the double-stranded nucleic acids comprise C6(OH)HDO, C9(OH)HDO, or C12(OH)HDO or any C6(OH)HDO-C12(OH)HDO without substituents (i.e., C6-C9 linear alkylenes without substituents)
Quantity of Experimentation
Considering the state of the art at the time of filing with respect to delivery of double-stranded oligonucleotides across the BBB into brain cells indicates that it is highly unpredictable, additional experimentation would be required to practice the claimed invention to the full scope encompassed by the claims. The additional experimentation required would amount to trial-and-error experimentation without a guarantee of success and any positive results would amount to a significant advancement in the state of the art.
Level of the skill in the art
The level of the skill in the art required to practice the claimed invention is deemed to be high, such as someone with an advanced degree in science such as a Ph.D. or M.D.
Conclusion
Considering the nature of the invention, the breadth of the claims, the unpredictable nature of the invention as recognized in the prior art, the limited amount of working examples and guidance provided, and the high degree of skill required to practice the invention, it is concluded that the specification does not provide an enabling disclosure for the full scope of the instant claims. Therefore, additional experimentation is required before one of skill in the art could make and use the claimed invention. The amount of additional experimentation required to perform the broadly claimed invention to its full scope is considered undue.
It is noted that limiting the scope of the claims to that which is enabled by the disclosure (i.e., see above), would obviate this rejection.
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 1-7, 9-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,433,089. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are broader in scope and fully encompass the claims of the ‘089 patent. Since a broad claim is anticipated by the narrower embodiments it encompasses, the instant claims are anticipated by the claims of the ‘089 patent and a non-statutory double patenting rejection is proper. See MPEP 804 II which states:
The claim under examination is not patentably distinct from the reference claim(s) if the claim under examination is anticipated by 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, 1052, 29 USPQ2d 2010, 2015-16 (Fed. Cir. 1993). This type of nonstatutory double patenting situation arises when the claim being examined is, for example, generic to a species or sub-genus claimed in a conflicting patent or application, i.e., the entire scope of the reference claim falls within the scope of the examined claim. In such a situation, a later patent to a genus would, necessarily, extend the right to exclude granted by an earlier patent directed to a species or sub-genus. In this type of nonstatutory double patenting situation, an obviousness analysis is not required for the nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to J. E. Angell whose telephone number is (571)272-0756. The examiner can normally be reached Monday-Friday (8:30-5:00).
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J. E. Angell
Primary Examiner
Art Unit 1637
/J. E. ANGELL, Ph.D./Primary Examiner, Art Unit 1637