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 with traverse of Group I (claims 1-6, 10, 12-14, 28-31, 33, and 34) in the reply filed on 05/11/2026 is acknowledged. The traversal is on the ground that Group I is used in the non-elected method of Group II.
Upon further consideration, the restriction requirement is withdrawn.
Claim Status
Claims 7-9, 11, 15-27, 32, 35-47, and 51 are cancelled. Claims 1-6, 10, 12-14, 28-31, 33, 34, 48-50, and 52 are pending and under review.
Claim Objections
Claim 3 objected to because of the following informalities: The claim recites “the aptamer of claims 1,” which is inappropriate because it depends from a single preceding claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112b
Claims 1-6, 10, 12-14, 28-31, 33, 34, 48-50, and 52 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.
The term “neutralizes” in independent claims 1, 28, and 48 render the scope of the claims unclear because neither the claims nor the specification defines what constitutes neutralization of an autoantibody, nor does it provide an assay or objective standard by which one could determine whether an aptamer falls within the scope of the claims. It is unclear whether neutralization requires binding alone, inhibition of antigen binding, inhibition of downstream biological activity, or some other effect, such that the metes and bounds of the claims cannot be determined with reasonable certainty. Dependent claims 2-6, 10, 12-14, 29-31, 33, 34, 49, 50, and 52 are also rejected as they implicitly or explicitly require the claimed neutralizing aptamer.
Furthermore, claim 12 recites the limitation “wherein the aptamers prevent demyelination.” There is insufficient antecedent basis for this limitation in the claim. For the purpose of examination, the term “aptamers” will be interpreted to be the singular “aptamer.”
Accordingly, claims 1-6, 10, 12-14, 28-31, 33, 34, 48-50, and 52 are rejected under 35 U.S.C. 112(b) as being indefinite.
Claim Rejections - 35 USC § 112a
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 1-3, 6, 10, and 12-14 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.
Independent claim 1 recites “an aptamer that neutralizes autoantibodies,” which encompasses a genus of aptamers. Claims 2-3, 10, and 12-14 are dependent from claim 1, do not materially limit the genus of agents, and are thus included in the rejection. 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. In the instant case, the only identifying characteristic present in the claim is the ability of “neutralizing autoantibodies,” however the specification only describes five species that bind to Myelin Oligodendrocyte Glycoprotein (MOG) autoantibodies [see drawings, FIG. 3A]. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics of the genus as a whole, or representative number of species within the genus, the specification does not provide adequate written description of the claimed genus.
Similarly, claim 6 recites an aptamer “at least 85%, 90%, or 95% identical to SEQ ID NO: 1,” thereby encompassing a genus of aptamers that are structurally similar to the claimed aptamer. The specification, however, fails to adequately describe the species of aptamer that are encompassed by the claim. There is no evidence in the specification to support that the inventors had possession of the genus contemplated. In the instant case, 5 aptamers are disclosed in SEQ ID NOs: 1-5, with FIG. 3A indicating binding properties. The disclosure fails to describe a representative number of species within the genus claimed and the specification does not identify which nucleotide substitutions may be made while retaining the claimed autoantibody neutralizing activity. Therefore, the specification fails to reasonably convey to one skilled in the relevant art that the inventor, at the time the application was filed, had possession of the claimed genus.
Therefore, claims 1-3, 6, 10, and 12-14 are rejected under 35 U.S.C. 112(a) for lack of written description.
Claim Rejections - 35 USC § 112d
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2 and 29 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. These claims recite wherein the aptamer “comprises nucleotides,” but because an aptamer is a nucleotide-based molecule, the limitation does not further restrict the scope of the claims from which they depend. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, and 12-14 are rejected under 35 U.S.C. 102a1 as being anticipated by Krasitskaya et al.
Claim 1 is drawn to an aptamer, claim 2 is drawn to the aptamer composition, and claims 12-14 are drawn to therapeutic use.
Krasitskaya et al. teaches that Myelin Basic Protein (MBP) autoantibodies contribute to the demyelination and pathogenesis of Multiple Sclerosis [see p. 113, col. 1, par. 1, lines 23-26]. Krasitskaya et al. discloses an RNA aptamer (aptamer Apt2-9c) that was generated by a SELEX method that utilizes biologically relevant native autoantibodies to MBP, and notes that this aptamer specifically binds to the antigen binding site of the MBP autoantibodies [see p. 114, col. 2, par. 3, lines 10-13]. More specifically, Krasitskaya et al. discloses that the SELEX method comprises adapting a library of ssDNA sequences into an RNA library, incubating the library with native autoantibodies, conducting 10 rounds of positive selection of aptamers that bind the antigen binding sites, and amplifying the bound RNA sequences [see Supplementary Material, p. S-5, par. 1-4]. Given that these autoantibodies target MBP and contribute to MS, these autoantibodies would be reasonably understood to exist in the central nervous system (CNS), but regardless, since instant claim 1 recites central or peripheral nervous system (PNS), the autoantibodies must necessarily fall into one of these categories (instant claim 1). Additionally, binding of the active site of these autoantibodies would reasonably be expected to interfere with, inhibit, or block the antibody’s ability to interact with its target antigen and would thus neutralize the antibody to some degree (instant claim 1). RNA aptamers inherently comprise nucleotides (instant claim 2). Claims 12-14 recite intended use, however the intended use does not materially affect the claimed structure. (instant claims 12-14).
Therefore, claims 1, 2, and 12-14 are rejected under 35 U.S.C. 102.
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.
Claims 1, 3, 48, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Krasitskaya et al. in view of Ray et al.
Claim 1 is drawn to an aptamer, claim 3 is drawn to an aptamer comprising ssDNA, and claims 48 and 50 are drawn to methods of identifying an aptamer.
The disclosure of Krasitskaya et al. is discussed above.
Krasitskaya et al. does not teach or suggest an aptamer comprising ssDNA.
Ray et al. teaches that RNA and DNA aptamers were recognized alternative platforms and that aptamers having comparable affinity and specificity could be generated from both RNA and DNA [see p. 1762, par. 2, lines 1-2]. Ray et al. teaches that DNA is a viable alternative, possessing its own advantages, including a lower cost of synthesis [see p. 1762, par. 2, lines 4-5 through to 1763, line 1]. Of note, while Ray et al. does not specifically note the DNA to be single stranded, a person having ordinary skill in the art would understand the aptamer to be single stranded, and furthermore, the instant specification defines aptamers as single stranded oligonucleotides [see par. 8, line 1].
It would have been obvious to a person having ordinary skill in the art to generate the aptamer of Krasitskaya et al. as a ssDNA aptamer with a reasonable expectation that the binding and neutralizing functionality would be retained because the art recognized that DNA aptamers are a functional alternative to RNA aptamers with the benefit of improved stability and lower cost of synthesis as discussed above (instant claim 3). Furthermore, to generate the ssDNA aptamer it would have been obvious to use the method disclosed by Krasitskaya et al. but modify the method to use the initial DNA library rather than modifying said library into an RNA library (instant claims 48 and 50) given that RNA libraries are used to generate RNA aptamers.
Therefore, claims 1, 3, 48, and 50 are rejected under 35 U.S.C. 103.
Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Krasitskaya et al. in view of Elliot et al.
Claim 1 is drawn to an aptamer and claim 4 is drawn to specific autoantibodies to be targeted.
The disclosure of Krasitskaya et al. is discussed above.
Krasitskaya et al. does not teach or suggest aptamers that inhibit autoantibodies to myelin oligodendrocyte glycoprotein (MOG) or Neurofascin (NFASC).
Elliot et al. discloses a bioassay to identify demyelinating autoantibodies in clinical samples [see p. 1820, col. 2, par. 2, lines 1-5]. To validate the bioassay, Elliot et al. utilizes a panel of antibodies against 11 autoantigens implicated in MS [see p. 1823, Fig. 1B, figure legend], thereby showing that the art recognized a finite set of pathogenic autoantibody targets relevant to MS at the time of the invention. Elliot et al. demonstrates that antibodies against MOG and Neurofascin (NFASC) in particular produce demyelination and axonal injury in vitro [see p. 1823, Fig. 1B, figure legend].
It would have been obvious to combine these teachings and generate an aptamer to inhibit MOG and NFASC autoantibodies because the art teaches that MOG, NFASC, and MBP are MS-associated autoantigen targets that facilitate demyelination, and these targets can be selected from a finite list of targets linked to pathogenic autoantibodies in MS. One would have been motivated to do so to generate similar aptamers against other known MS autoantibodies and improve patient outcomes. One would have had a reasonable expectation of success because SELEX was a routine platform adaptable to different antibody targets, and neutralizing these autoantibodies would be expected to prevent or slow demyelination (instant claim 4).
Therefore, claims 1 and 4 are rejected under 35 U.S.C. 103.
Claims 1, 10, 28, 29, 31, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Krasitskaya et al. in view of Islam et al.
Claim 1 is drawn to an aptamer, claim 10 is drawn to an aptamer comprising an additional peptide moiety, claim 28 is drawn to administering an aptamer, claims 29 and 31 are drawn to further compositions of an aptamer, and claim 34 is drawn to specific diseases treated by administration of an aptamer.
The disclosure of Krasitskaya et al. is discussed above.
Krasitskaya et al. does not teach or suggest an additional peptide moiety to increase the ability of the aptamer to cross the blood brain barrier (BBB).
Islam et al. teaches that shuttle peptides may facilitate the influx of a diverse range of small molecule cargo across the BBB [see p. 5, par. 1, line 1]. Islam et al. further teaches that aptamers had been successfully conjugated to shuttle peptides and these aptamer-peptide conjugates showed permeability across the BBB both in vivo and in vitro [see p. 5, par. 2, lines 18-21 through p. 7, par. 1, lines 1-3].
It would have been obvious to one seeking to improve the delivery of Krasitskaya et al.’s aptamer to the CNS to combine these teachings and conjugate the aptamer to a peptide moiety that increases its BBB permeability because the aptamer is targeted to autoantibodies of the CNS and shuttle peptides bound to aptamers were known in the art as a useful mechanism to cross the BBB (instant claim 10). One would have been motivated to do so to increase the efficacy of the aptamer and provide better therapeutic outcomes.
Additionally, it would have been similarly obvious to administer an effective amount of said conjugated aptamer, which inherently comprises nucleotides (instant claim 29), to a subject in need, because the art teaches that the aptamer is capable of inhibiting pathogenic autoantibodies that contribute to MS-associated demyelination as discussed above (instant claims 28 and 31). Administration would have represented therapeutic use of a known inhibitor of a known pathogenic target, using a known delivery mechanism to access the target site. Furthermore, the instant specification defines treatment as “therapeutic and preventative measures wherein the object is to prevent or slow the development of the disease” to include “preventing it from worsening.” Given that autoantibodies towards MBP contribute to demyelination and the progression of MS, it would be obvious and expected that neutralizing said antibodies would prevent or slow demyelination, and similarly prevent or slow MS development to some degree (instant claims 28 and 34).
Therefore, claims 1, 10, 28, 29, 31, and 34 are rejected under 35 U.S.C. 103.
Claims 28 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Krasitskaya et al. and Islam et al., and in further view of Elliot et al.
Claim 28 is drawn to administering an aptamer and claim 33 is drawn to administering an aptamer that neutralizes specific autoantibodies.
The disclosures of Krasitskaya et al. and Islam et al. are discussed above.
The combination of these references does not teach or suggest administering an aptamer that neutralizes MOG or NFASC.
The disclosure of Elliot et al. is discussed above.
It would have been obvious to combine these teachings and administer an effective amount of an aptamer that neutralizes MOG or NFASC autoantibodies as the prior art recognized MOG and NFASC autoantibodies as clinically relevant targets in demyelinating disease, identifies ways to generate clinically relevant aptamers targeting those autoantibodies. Furthermore, one would have had an expectation of success as the inhibition of autoantibodies that induce demyelination would have been expected to reduce demyelination and provide therapeutic effects in MS as discussed above (instant claim 33).
Therefore, claims 28 and 33 are rejected under 35 U.S.C. 103.
Claims 28 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Krasitskaya et al. and Islam et al., and in further view of Ray et al.
Claim 28 is drawn to administering an aptamer and claim 30 is drawn to administering an ssDNA aptamer.
The disclosures of Krasitskaya et al. and Islam et al. are discussed above.
The combination of these references does not teach or suggest administration of a ssDNA aptamer.
The disclosure of Ray et al. is discussed above.
It would have been obvious to combine these teachings and administer the aptamer of Krasitskaya et al. as an ssDNA aptamer because the art recognized aptamers as therapeutically translatable and further recognized DNA aptamers as a known functional alterative to RNA aptamers. The prior art additionally taught that aptamers having comparable affinity could be generated from either DNA or RNA. Given this, a person having ordinary skill in the art would have therefore had a reasonable expectation that the binding and neutralizing functionality would be retained (instant claim 30).
Therefore, claims 28 and 30 are rejected under 35 U.S.C. 103.
Claims 48 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Krasitskaya et al. in view of Ray et al., and in further view of Bognar et al.
Claims 48 and 49 are drawn to a method of identifying an aptamer.
The disclosure of Krasitskaya et al. and Ray et al. are discussed above.
The combination of Krasitskaya et al. and Ray et al. do not teach or suggest removing ssDNA sequences that bind to the Fc region.
Bognar et al. teaches that autoimmune diseases are associated with the production of IgG and IgM autoantibodies [see p. 5, par. 4, lines 1-2]. Bognar et al. further teaches that IgG antibodies contain conserved Fc domains that are shared among antibodies of the same species [see p. 13, par. 4, lines 1-2]. Because Fc regions are conserved, aptamer selection against antibodies can result in enrichment of non-specific Fc-binding aptamers rather than aptamers directed to the desired variable region. Bognar et al. teaches excluding Fc-binding aptamers through counter-selection against Fc the domain [see p. 13, par. 4, lines 2-3]. Bognar et al. teaches that counter-selection occurs prior to amplification [see p. 2, figure 1].
It would have been obvious to apply the disclosed Fc counter-selection method when performing SELEX with native autoantibodies, particularly with IgG autoantibodies, as they contain the same conserved Fc domains responsible for non-specific Fc binding. Doing so would have been a predictable application of a known SELEX optimization method, yielding the expected result of enriching for aptamers that bind the desired variable region rather than non-specific Fc-binding sequences.
Therefore, claims 48 and 49 are rejected under 35 U.S.C. 103.
Claims 48 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Krasitskaya et al. in view of Ray et al., and in further view of Elliot et al.
Claims 48 and 52 are drawn to a method of identifying an aptamer.
The disclosure of Krasitskaya et al. and Ray et al. are discussed above.
The combination of these references does not teach or suggest that the antibodies used in the SELEX method are autoantibodies towards MOG or NFASC.
The disclosure of Elliot et al. is discussed above.
It would have been obvious to apply the disclosed Fc counter-selection method of Krasitskaya et al., as modified by Ray et al., to MOG and NFASC recognizing autoantibodies because these autoantibodies were recognized pathogenic targets associated with demyelinating disease. One seeking to develop therapeutic aptamers for MS and related demyelinating conditions would have been motivated to select MOG and NFASC autoantibodies because they represent clinically relevant mediators of disease pathology on a short list of possible therapeutic targets. Furthermore, one would have had a reasonable expectation of success in identifying a neutralizing aptamer against these targets because the art demonstrated that SELEX-based approaches, particularly those using native autoantibodies, could be used to generate aptamers capable of binding and modulating pathogenic autoantibodies.
Therefore, claims 48 and 52 are rejected under 35 U.S.C. 103.
Art-Free Subject Matter
The prior art does not teach or suggest the specific sequence of SEQ ID NO: 1. However, claim 5 remains subject to the outstanding rejections under 35 U.S.C. 112. Should applicant overcome the outstanding rejections and claim 5 be rewritten in independent form, including all of the limitations of the base claim and any intervening claims, this claim may be allowable.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tirone D Johnson whose telephone number is (571)272-1256. The examiner can normally be reached M-F, 9-5 ET.
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/TIRONE D. JOHNSON/ Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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