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
Species Election
This application contains claims directed to more than one species of the generic invention. These species are deemed to lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1.
The species are as follows:
Species A: The antisense oligonucleotides of SEQ ID NOs: 190-546 in claims 54-57 and 67-70.
Applicant is required, in reply to this action, to elect a single species to which the claims shall be restricted if no generic claim is finally held to be allowable. The reply must also identify the claims readable on the elected species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered non-responsive unless accompanied by an election.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which are written in dependent form or otherwise require all the limitations of an allowed generic claim. Currently, the following claim(s) are generic: 51 and 61.
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
The chemical compounds of SEQ ID Nos: 190-546 are not regarded as being of similar nature because: (1) the alternatives do not all share a common structure and (2) the alternatives do not all belong to a recognized class of chemical compounds. In the instant case, the antisense oligonucleotides of SEQ ID NOs: 190-546 have different nucleotide sequences and target different portions of SEQ ID NO: 1. There is no common core sequence amongst the ASOs of SEQ ID NOs: 190-546.
During a telephone conversation with Jeannie Brashear on 12/17/2025, a provisional species election was made without traverse to prosecute the antisense oligonucleotide of SEQ ID NO: 319. Affirmation of this election must be made by applicant in replying to this Office action.
Upon further consideration, the species election requirement is withdrawn and the antisense oligonucleotides of SEQ ID NOs: 190-546 are examined.
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 06/18/2025 is acknowledged. Claims 1-50 were canceled and new claims 51-72 were added.
Claims 51-72 are pending and under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. See Fig. 21F and 29G showing nucleotide sequences with no sequence identifier. The SEQ ID NOs do not appear in the Brief Description of the Drawings in paragraphs 0057 and 0065.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The examiner acknowledges the priority entitlement date of December 9, 2020 as the priority document GB2019418.9 provides support for the instant claims on pages 3,16-18 and 24-28.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See at least page 157 [0504] and page 163 [0526] and [0527] which contain hyperlinks.
Claim Objections
Claim 55 is objected to because of the following informalities: claim 55 is missing a period after “55”. In addition, line 2 of claim 55 recites “wherein the uracils in SEQ ID NOs: 190-546 are placed with thymines” and should recite “replaced” as in claim 57. Appropriate correction is required.
Claim 62 is objected to because of the following informalities: claim 62 recites “FOSMN” in line 3. The claim should recite the full name of the disease for clarity. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 71 and 72 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 71 recites the limitation "the method of claim 57" in line 1. Claim 57 is not a method claim and recites “the antisense oligonucleotide…”. There is insufficient antecedent basis for this limitation in the claim.
Claim 72 recites the limitation "the method of claim 71" in line 1. As stated above claim 71 depends on claim 57, which does not recite a method but rather a product, “the antisense oligonucleotide…”. There is insufficient antecedent basis for this limitation in the claim.
Written Description Rejection
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 51-53,58-66,71 and 72 are rejected under 35 U.S.C. 112, first paragraph,
as failing to comply with the written description requirement. The claim(s) 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(s), at the time the
application was filed, had possession of the claimed invention.
Claims 51 and 58-60 encompass an antisense oligonucleotide 13-30 nucleotides in length that is complementary to at least any 13 nucleotides of SEQ ID NO: 1 and which has the function of reducing expression of the UNC13A cryptic exon splice variant of UNC13A mature mRNA in a cell. SEQ ID NO: 1 is 1288 nucleotides in length, and therefore the claims encompass that the antisense oligonucleotide is complementary to at least 13 nucleotides of any region of SEQ ID NO: 1 and result in the recited function. Claim 52 encompasses any antisense oligonucleotide that is 13-30 nucleotides in length and that is complementary to at least any 13 nucleotides or SEQ ID NO: 2, which is 128 nucleotides in length and claim 53 encompasses any antisense oligonucleotide that is 13-30 nucleotides in length and that is complementary to at least any 13 nucleotides of SEQ ID NO: 3, which is 178 nucleotides in length and results in the recited function of reducing expression of the UNC13A cryptic exon splice variant of UNC13A mature mRNA in a cell. Claims 54-57 and 67-70 encompass specific nucleotide sequences of SEQ ID NOs: 190-546, and therefore are not included in the rejection.
Claim 61 encompasses a method of treating any neurodegenerative disorder associated with TDP-43 pathology in a subject comprising administering to the subject the antisense oligonucleotide of claim 51 in amount effective to treat the neurodegenerative disorder and therefore encompasses administering the antisense oligonucleotide that is 13-30 nucleotides in length and is complementary to at least any 13 nucleotides of any region of SEQ ID NO: 1 and results in the recited function. Claims 62-64 recite specific neurodegenerative disorders, amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, FOSMN, or Perry Syndrome. Claim 65 encompasses a method of treating any neurodegenerative disorder associated with TDP-43 pathology in a subject comprising administering to the subject any antisense oligonucleotide that is 13-30 nucleotides in length and that is complementary to at least 13 nucleotides or SEQ ID NO: 2, which is 128 nucleotides in length and claim 66 encompasses administering any antisense oligonucleotide that is 13-30 nucleotides in length and that is complementary to at least 13 nucleotides or SEQ ID NO: 3, which is 178 nucleotides in length and results in the recited function. Claims 71 and 72 recite dependency on claim 57 which is a product claim, however recite a method in the preamble. Therefore, the examiner is interpreting claim 71 to depend on claim 61 similar to how claim 58 reciting similar subject matter depends on independent claim 51.
The specification discloses SEQ ID NO: 1 as a portion of UNC13A transcribed mRNA intron sequence with cryptic exon-cords, chr19:17,641,557-17642844 and shows the sequence on pages 130-131 and that the long variant (SEQ ID NO: 3) is underlined, the shorter variant is in italics (SEQ ID NO: 2), and the SNPs are bolded and the branch points are highlighted and lower case bases denote the bases immediately flanking the splice sites (paragraph 0492).
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250
647
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The specification discloses ASO sequences that bind to crucial elements involved in UNC13A cryptic exon splicing, starting in Table 1 on page 132 which include SEQ ID NOs: 4-104 which target the branchpoint, Table 2, pages 136-143 SEQ ID NOs: 105-189 that target the 3’-splice site, SEQ ID NOs: 270-352 that target the 5’-splice site, Table 3, pages 143-156 SEQ ID NOs: 190-269 that target the cryptic site, SEQ ID NOs: 353-426 that target the intron SNP, SEQ ID NOs: 427-474 that target the downstream TDP-43 binding site, and SEQ ID NOs: 475-546 that target the enhancer. However, as seen above in SEQ ID NO: 1, there are portions of SEQ ID NO: 1 that do not contain the branchpoint, splice sites, cryptic sites, intron SNP, TDP-43 binding site and enhancer and that the disclosed antisense oligonucleotides do not target.
For example, SEQ ID NO: 4 is complementary to nucleotides 146-134 of instant SEQ ID NO: 1 as shown in the alignment below:
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66
216
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However, SEQ ID NO: 4 is only complementary to 8 nucleotides of instant SEQ ID NO: 2 and instant SEQ ID NO: 3:
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66
141
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67
137
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As another example, the ASO of SEQ ID NO: 427 which targets a downstream TDP-43 binding site is complementary to 13 nucleotides 1041-1029 of instant SEQ ID NO: 1:
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67
198
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However, the alignments below show the complementarity of SEQ ID NO: 427 to SEQ ID NOs: 2 and 3 respectively, and show that SEQ ID NO: 427 is not complementary to at least 13 nucleotides of instant SEQ ID NOs: 2 or 3:
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64
160
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64
177
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Therefore, not all of the antisense oligonucleotides that are complementary to 13 nucleotides of portions of SEQ ID NO: 1 are complementary to 13 nucleotides of SEQ ID NOs: 2 or 3, and the disclosed antisense oligonucleotides do not target the entire range of nucleotides of SEQ ID NO: 1 and result in the recited functions.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, the specification discloses ASO sequences that bind to portions of instant SEQ ID NO: 1,2 and 3. However, as seen above, the specification does not provide written description for the genus of ASO sequences that are complementary to 13 nucleotides of the entire range of nucleotides of instant SEQ ID NOs: 1,2 or 3. While the genus encompasses a large number of antisense oligonucleotide sequences that have the same activity, the genus of antisense oligonucleotides encompasses a large number of molecules that have a different structure (nucleotide sequence), and the specification does not describe a common core structure of the species of the large genus of antisense oligonucleotides 13-30 nucleotides in length, complementary to at least 13 nucleotides of instant SEQ ID NO: 1,2 or 3 and which result in the functional limitations of the instant claims (reducing expression of the UNC13A cryptic exon splice variant of UNC13A mature mRNA in a cell; Treating a neurodegenerative disorder associated with TDP-43 pathology in a subject).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
With the exception of the antisense oligonucleotides of SEQ ID NOs:190-546, the skilled artisan cannot envision the detailed chemical structure of the encompassed antisense oligonucleotides with the functions recited in the instant claims. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Next, then, it is determined whether a representative number of species have
been sufficiently described by other relevant identifying characteristics (i.e. other than
nucleotide sequence), specific features and functional attributes that would distinguish
different members of the claimed genus. To the extent that a functional description can
meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003). In the instant case, no identifying characteristics of the antisense oligonucleotides are disclosed. Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163). Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, Applicant’s disclosure of the species of antisense oligonucleotides of SEQ ID NOs:190-546 of the claimed broad genus of antisense oligonucleotides that are 13-30 nucleotides in length and complementary to at least any 13 nucleotides of SEQ ID NOs: 1,2 or 3 is not deemed sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genus at the time the application was filed. Thus it is concluded that the written description requirement is not satisfied for the claimed genus.
Scope of Enablement Rejection
Claims 61-72 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 amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprising directly administering the antisense oligonucleotides of SEQ ID NOs: 555-571,579 and 580 to the central nervous system of the subject, the specification is not enabling for the claimed method of treating a genus of neurodegenerative disorders associated with TDP-43 pathology in a subject, wherein the subject is administered the antisense oligonucleotides of 13-30 nucleotides in length and that is complementary to at least 13 nucleotides of SEQ ID NO: 1,2 or 3, or the unmodified antisense oligonucleotides comprising SEQ ID NOs: 190-546, by other routes of administration. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The Breadth of the Claims and The Nature of the Invention
Based on the broadest reasonable interpretation, claims 61-72 encompass a method of treating any neurodegenerative disorder associated with TDP-43 pathology in a subject comprising administering any antisense oligonucleotide that is 13-30 nucleotides in length and that is complementary to at least 13 nucleotides of SEQ ID NO: 1,2 or 3 or the antisense oligonucleotides of SEQ ID NOs: 190-546, comprising any route of administering of the antisense oligonucleotide. For the claims to be enabled for the full scope, the recited ASOs would need to reach the lesions in neuronal cells or affected cells, be able to inhibit aberrant splicing at the cryptic splice site and increase the production of functional protein, consequently resulting in treatment of the neurodegenerative disorder associated with TDP-43 pathology in a subject (ALS, FTD, Alzheimer’s disease, Parkinson’s disease, FOSMN, or Perry Syndrome).
The State of the Prior Art
At the time of the filing of the application, in vivo delivery of ASOs to cells of a subject, particularly to brain or neuronal cells has challenges. Systemically administered ASOs are usually cleared by nuclease degradation, hepatic and renal systems and other mechanisms and only small fractions reach a target cell. Additionally, delivery to CNS has its own obstacle of blood brain barrier.
Roberts et al. (Nature Reviews: Drug Discovery Vol. 19, October 2020, pages 673-693) teach the challenges of effective delivery of oligonucleotide therapeutics to many tissues, and that systemic delivery to the central nervous system has an additional challenge of oligonucleotide-based therapeutics that are generally not able to traverse the blood-brain barrier (page 677, right column). Roberts et al. teach the majority of oligonucleotide therapeutics focus on either local delivery or delivery to the liver (page 677, right column), or direct injection of oligonucleotides into the cerebrospinal fluid by lumbar puncture for distribution through the CNS (page 679, left column). Finally, Roberts et al. teach “the establishment of therapeutic platforms capable of delivering oligonucleotide drugs to specific organs or tissues will likely involve defined patterns of chemical modification, combined with conjugation/complexation strategies that confer predictable pharmacokinetic and pharmacodynamic properties and well-understood mechanisms of action” (page 689, left column).
Likewise, Kuijper et al. (J Inherit Metab Dis, 3 June 2020, pages 72-87) teach systemic delivery of single-stranded antisense oligonucleotides with a PS backbone is feasible, as the majority of the antisense oligonucleotide will be taken up by the liver and kidney and some uptake by most other tissues with the exclusion of the nervous system, as most AON chemistries cannot cross the blood-brain barrier (Section 2.2, page 74).
Bennett et al. (Annu Rev Neurosci 08 July 2019; 42: 385-406) teach that molecular mechanisms through which an ASO modulates RNA functions are dependent on the chemical modifications, the position of modifications and where in the target RNA the oligonucleotide binds (Antisense Therapeutics, pages 2-3). Bennett et al. teach that chemical modifications have a major impact on pharmacokinetic properties of ASO drugs, and that single-stranded phosphorothioate-modified ODNs and phosphorothioate-modified chimeric DNA/2’-sugar oligonucleotides distribute broadly when administered systemically, with the highest concentrations in the kidney, liver, spleen and lymphatic tissues, and that the amount of phosphorothioate ODNs that cross the blood-brain barrier is not sufficient for pharmacological activity (page 3 bottom). While Bennet et al. teach injection of single-stranded phosphorothioate-modified and 2’-MOE modified ASOs into the CSF resulted in rapid distribution throughout the spinal cord and into most brain regions, and that intrathecal administration shows highest drug concentrations in the lumbar spinal cord and cortical regions of the brain (page 4, first paragraph), there is no guidance whether an ASO that targets aberrant splicing of UNC13A would reach neuronal cells affected by ALS in effective amounts to be able to inhibit the aberrant splicing.
Therefore, the state of the art shows that a method of delivering ASOs to brain and neuronal cells in general and to ALS lesions in particular had challenges and was unpredictable at the time of the filing of the instant specification. The art cited above suggests that a vast amount of experimentation is needed to enable a method of delivering ASOs to brain and neuronal cells in general and to ALS lesions in a subject in vivo, and testing and determining the appropriate route of administration.
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable. If one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains (i.e. a method of treating a neurodegenerative disorder associated with TDP-43 pathology in a subject, comprising administering to the subject the antisense oligonucleotide of 13-30 nucleotides in length and that is complementary to at least 13 contiguous nucleotides of SEQ ID NO: 1,2 or 3, or the antisense oligonucleotides comprising the nucleotide sequence set forth in any one of SEQ ID NOs: 190-546), then there is a lack of predictability in the art. Moreover, it is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. The court has indicated that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species, what other species will work.
The lack of predictability stems from the lack of evidence that the method when carried out in vivo in a subject will result in treatment of the neurodegenerative diseases associated with TDP-43 pathology, including ALS, FTD, Alzheimer’s disease, Parkinson’s disease, FOSMN or Perry Syndrome and the lack of guidance regarding the route of administration that will result in the treatment of any of the encompassed neurodegenerative diseases. Since the specification only exemplifies in-vitro cell models and does not demonstrate any data or evidence that the recited ASOs would result in treatment of any of the recited neurodegenerative disorders when administered by any route of administrations to a subject, there would be no way of determining without undue experimentation whether the recited ASOs exhibits such a desired result. Therefore, without more experimentation demonstrating the efficacy of the claimed ASOs, the level of unpredictability remains high and it is unpredictable that the claimed ASOs that are complementary to at least 13 contiguous nucleotides of SEQ ID NO: 1,2 or 3 or the ASOs comprising SEQ ID NOs: 190-546 will result in treating the genus of neurodegenerative disorders associated with TPD-43 pathology in a subject by a genus of routes of administration.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
The specification does not enable any person skilled in the art to which it pertains (i.e. a method of treating a neurodegenerative disorder associated with TDP-43 pathology in a subject comprising administering to the subject the antisense oligonucleotide 13-30 nucleotides in length and that is complementary to at least 13 contiguous nucleotides of SEQ ID NO: 1,2 or 3, or the antisense oligonucleotides comprising SEQ ID NOs: 190-546), to make and/or use the invention commensurate in scope with the claims. There is a lack of adequate guidance from the specification or prior art with regard to the method being carried out in vivo regarding the route of administration of the genus of antisense oligonucleotides and the genus of neurodegenerative disorders associated with TDP-43 being treated.
The specification discloses that the present disclosure relates to novel therapeutics for treatment of neurodegenerative disorders, more particularly ALS and FTD, or those associated with TDP-43 pathology (paragraph 0002), and that TDP-43 is depleted from the nucleus and accumulated in cytoplasm inclusions in a number of neurodegenerative disorders, including >95% ALS cases and approximately 50% TFD cases, approximately 30% of Alzheimer disease cases, Parkinson disease and other rare neurodegenerative disorders (paragraph 0005). The specification discloses the novel cryptic exon in UNC13A was detected in patient postmortem brain regions affected by TDP-43 proteinopathy, including both ALS and FTD and was found to overlap with the disease-associated variant rs12973192 that was previously identified as linked to ALS/FTLD risk and disease aggressiveness (paragraph 0034). Therefore, the instant specification shows the link between the novel cryptic exon in UNC13A and ALS and FTD affected by TDP-43 proteinopathy, but does not describe the link with other TDP-43 pathologies.
The specification discloses that the method of delivering an antisense polynucleotide to a cell, wherein the ASO modulates splicing of UNC13A to prevent inclusion of a cryptic exon in UNC13A RNA, may be an in vitro or an in vivo method, (paragraph 0382), however the specification does not provide any guidance as to how to deliver the claimed ASO to a subject. Since the delivery of ASO is intended to brain lesions or neuronal cells in a subject that have TDP-43 dysfunction or cryptic splice event, the ASO would need to be delivered to the brain or neuronal cells to be able to inhibit cryptic splice site as claimed. The specification does not provide any guidance regarding delivering the ASO to the brain or neuronal cell of a subject.
The specification discloses the detection of UNC13A cryptic event in patient samples (paragraph 0488); characterization of SEQ ID NO: 1 comprising minor allele of the SNP (the risk variant) or the major allele at rs12973192 and/or rs12608932 and that SEQ ID NO:1 also encompasses the sequence wherein the emboldened G (at rs12973192) is replaced with a C, and the emboldened U (rs12608932) corresponding to the rs12608932 cryptic exon SNP may be replaced with a G (paragraph 0495). The specification further discloses that SEQ ID NO: 2 is the shorter UNC13A cryptic exon sequence which may encompass the minor allele of the SNP (the risk variant) or the major allele at rs12973192 and also encompasses the sequence wherein the emboldened G (at rs12973192) is replaced with a C (paragraph 0496), and SEQ ID NO: 3 is the longer UNC13A cryptic exon sequence which may encompass the risk variant of the SNP (the risk variant), or the major allele at rs12973192, and the sequence wherein the emboldened G (at rs12973192) is replaced with C (paragraph 0497).
The specification shows in Example 7, Table 5 on pages 158-159 ASO sequences tested for rescue effect against the UNC13A cryptic exon, and the sequences are SEQ ID NOs: 555-571,579 and 580 and these sequences have specific modifications including phosphorothioate, LNA and 2’-O-methyl RNA. It is not clear what sequences these modified sequences correspond to regarding the range of SEQ ID NOs: 4-546. The ASO’s of SEQ ID NOs: 555-571,579 and 580 were transfected into SK-N-DZ cells with TDP-43 knockdown, and these human, neuron-like cells have been previously demonstrated to replicate numerous aberrant splicing events found in ALS/FTD patients and are a suitable model (paragraph 0510). The results are shown in Figures 14A and 14B, paragraph 0511-0513, Figure 17, paragraph 0516. Example 8 and Figure 33 shows the ability of ASOs to induce the correct splicing event in disease-state cells and that the ASOs targeting donor splice site can rescue the splicing in SHSY5Y cells (paragraph 0521).
None of the examples provide any guidance regarding delivering of the claimed ASO to the brain or a neuronal cell of a subject that has an increase in the inclusion of cryptic splice in mature RNA and there is no evidence of record that such can be achieved in vivo in a subject. The amount of direction or guidance presented in the specification regarding the method being carried out in vivo comprising administering the ASO of claims 51-72 to a subject and resulting in treatment of a neurodegenerative disorder associated with TDP-43 pathology is limited, as the examples only pertain to in-vitro cell models. The specification provides no evidence that administering the claimed ASOs would result in treatment of a neurodegenerative disorder associated with TDP-43 pathology in a subject, and therefore does not provide adequate support for the breadth of the instant claims. As previously shown in the state of the prior art, neurodegenerative diseases require particular routes of administration (e.g. intrathecal) in order for the therapeutic oligonucleotide to reach the desired cell/tissue in the CNS.
The Quantity of Experimentation Necessary
In light of the unpredictability surrounding the claimed subject matter, and the lack of adequate guidance, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Absent a reasonable a priori expectation of success for administering by any route of administration, an antisense oligonucleotide of 13-30 nucleotides in length and that is complementary to at least 13 contiguous nucleotides of SEQ ID NO: 1,2, or 3 or the antisense oligonucleotides of SEQ ID NOs: 190-546, to treat any neurodegenerative disorder associated with TDP-43 pathology in a subject, one skilled in the art would have to extensively test the ASOs in vivo in an appropriate model of these diseases. Since each prospective embodiment, and indeed future embodiments as the art progresses, would have to be empirically tested, and those which initially failed tested further, an undue amount of experimentation would be required to practice the invention as it is claimed in its current scope, because the specification provides inadequate guidance to do otherwise. Therefore, without any evidence that the claimed method of administering by any route of administration of the recited ASOs would provide a treatment effect for ALS, FTD, Alzheimer’s disease, Parkinson’s disease, FOSMN or Perry Syndrome, a person of ordinary skill in the art would reasonably require an undue quantity of experimentation.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
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 61-72, in view of the applicant’s entire disclosure and considering the In re Wright decision discussed above, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 61-72 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 use the invention commensurate in scope with these claims.
Claim Rejections - 35 USC § 102
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.
Claim Interpretation: For the following 35 U.S.C. 102(a)(1) rejections, the “wherein clause” in claim 51, “wherein the oligonucleotide reduces expression of the UNC13A cryptic exon splice variant of UNC13A mature mRNA in a cell” is not being considered as a claim limitation as it does not limit the claim to a particular structure. Therefore, art that teaches an antisense oligonucleotide comprising a nucleotide sequence 13-30 nucleotides in length and that is complementary to at least 13 nucleotides of instant SEQ ID NO: 1,2 or 3 meets the required structure of claims 51-53 and would read on the claims, and the “wherein clause” would be a result of the recited structure. See MPEP 2111.04.
In addition, sequences that are complementary to at least 13 nucleotides of instant SEQ ID NOs: 2 and 3 would also be complementary to at least 13 nucleotides of SEQ ID NO: 1 as SEQ ID NOs: 2 and 3 fall within SEQ ID NO: 1.
Claim 51 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Meissner et al. (US 20190309259, Published 10 Oct 2019).
Regarding claim 51, Meissner et al. teach ribonucleic acids comprising a sequence selected from the group consisting of SEQ ID NOs: 2-817976 (paragraph 0205). Nucleotides 20-1 of SEQ ID NO: 79449 of Meissner et al. are complementary to nucleotides 791-810 of instant SEQ ID NO:1. SEQ ID NO: 79449 is identified as a gRNA sequence below. Therefore, Meissner et al. teach an antisense oligonucleotide 20 nucleotides in length and complementary to 20 nucleotides of instant SEQ ID NO: 1. As the structure of the gRNA of SEQ ID NO: 79449 meets the structural limitations recited by instant claim 51, the function of the oligonucleotide reducing expression of UNC13A cryptic exon splice variant of UNC13A mature mRNA in a cell would be carried out.
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Claims 51-53 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bentwich (U.S. Patent No. 7,655,785, Patented 2 Feb 2010).
Regarding claims 51-53, Bentwich teach human regulatory microRNA-like oligonucleotides referred to as Genomic Address Messenger (GAM) oligonucleotides, which inhibits translation of one or more target genes by hybridization of an RNA transcript encoded by the GAM to a site located in an UTR of the mRNA of one or more target genes (Column 3, lines 52-61). Bentwich teach the oligonucleotides of the invention comprise non-protein coding oligonucleotides which modulate expression of thousands of proteins and are associated with numerous major diseases (Column 4, lines 34-38), as well as improved methods and systems for specific modulation of the expression of specific target genes involved in significant human diseases, and for detection of the expression of oligonucleotides of the invention which modulate these target genes (Column 4, lines 63-67 to Column 5 lines 1-2). Therefore, the purpose of Bentwich is to find oligonucleotides that are regulatory elements, and discusses the use of these oligonucleotides for modulation of the expression of target genes associated with diseases, and Bentwich teach inhibitory oligonucleotide sequences as discussed below, and will have the function as claimed.
Bentwich teach isolated oligonucleotides which anneals to a portion of an mRNA transcript of a target gene, wherein binding of the oligonucleotide to the mRNA transcript represses expression of the target gene, and wherein the oligonucleotide has at least 80% sequence identity with the complement of a sequence selected from the group consisting of SEQ ID NOs: 1555476-1616125; SEQ ID NOs: 1656865-1680643 (Colum 38 lines 55-67 to Column 39 line 3 and Column 40, lines 1-15). Below are alignments of the sequences of Bentwich which are complementary to instant SEQ ID NOs: 2 and 3. As seen in the alignments below, the oligonucleotides of Bentwich are between 13-21 nucleotides in length and are complementary to at least 13 nucleotides of SEQ ID NOs: 2 and 3.
Qy is instant SEQ ID NO: 2, Db is SEQ ID NO: 1611900 of Bentwich:
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201
568
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO: 1611900 of Bentwich:
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194
565
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO: 1678132 of Bentwich:
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205
567
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO: 1678132 of Bentwich:
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195
563
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO: 1669354 of Bentwich:
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198
557
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO: 1669354 of Bentwich:
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194
558
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO: 1679507 of Bentwich:
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185
559
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO: 1679507 of Bentwich:
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185
559
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO: 1660835 of Bentwich:
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180
553
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO: 1660835 of Bentwich:
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Claims 51-53 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rigoutsos et al. (U.S. Patent No. 8,178,503 Patented 15 May 2012).
Regarding claims 51-53, Rigoutsos et al. teach ribonucleic acid interference molecules (Field of Invention, column 1), and sequences that can be used in the context of gene regulation, referred to as “pyknons”, comprising SEQ ID NOs: 1-747326 (Summary of Invention, Column 1). Rigoutsos et al. teach determining associations between non-coding and gene-coding sequences in the genome of an organism, which includes that the identified conserved regions (conserved motifs) of the intergenic/intronic non-coding sequences are linked to gene coding regions of the genome, and these identified sequences link the coding an non-coding region of the genome which provides for an association to be made with the biological processes of the organism (Column 3, lines 52-54 and Column 4, lines 4-19,59-61). Rigoutsos et al. teach methods for regulating the expression of a transcript comprises using at least one of SEQ ID NOs: 1-747326 to design an interfering RNA molecule that contains a region the corresponds to the reverse complement of one or more sequences having SEQ ID NOs: 1-747326 (Column 2, lines 9-16). Therefore, Rigoutsos et al. teach oligonucleotides which are regulatory elements and teach inhibitory sequences as discussed below and which will have the function as claimed.
Below are alignments of the sequences of Rigoutsos et al. which are complementary to instant SEQ ID NOs: 2 and 3. As seen in the alignments below, the oligonucleotides of Rigoutsos et al. are between 13-16 nucleotides in length and complementary to at least 13 nucleotides of SEQ ID NOs: 2 and 3.
Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:48759 of Rigoutsos:
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189
566
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:48759 of Rigoutsos:
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184
555
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:106708 of Rigoutsos:
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185
552
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:106708 of Rigoutsos:
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185
557
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:367147 of Rigoutsos:
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183
548
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:367147 of Rigoutsos:
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185
550
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:393218 of Rigoutsos:
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180
555
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:393218 of Rigoutsos:
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178
552
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:590896 of Rigoutsos:
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191
548
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO: 590896 of Rigoutsos:
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186
551
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:606247 of Rigoutsos:
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183
546
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:606247 of Rigoutsos:
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199
559
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:647478 of Rigoutsos:
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189
550
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:647478 of Rigoutsos:
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194
551
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:666012 of Rigoutsos:
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188
549
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:666012 of Rigoutsos:
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549
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Claims 51-53 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krieg et al. (U.S. Patent No. 10,058,623 Patented 28 Aug 2018).
Regarding claims 51-53, Krieg et al. teach single stranded oligonucleotides that have a region of complementarity that is complementary with at least 8 consecutive oligonucleotides of a PRC2-associated region of a UTRN gene (Column 2, lines 29-33), and the single stranded oligonucleotide comprises a nucleotide sequence as set forth in SEQ ID NOs: 463-497728 (Column 3, lines 29-31).
Below are alignments of the sequences of Krieg et al. which are complementary to instant SEQ ID NOs: 2 and 3. As seen in the alignments below, the oligonucleotides of Krieg et al. are between 15 nucleotides in length and complementary to at least 13 nucleotides of SEQ ID NOs: 2 and 3.
Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:311552 of Krieg:
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:311552 of Krieg:
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190
547
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:311554 of Krieg:
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551
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:311554 of Krieg:
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Qy is instant SEQ ID NO: 2, Db is SEQ ID NO:311555 of Krieg:
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554
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Qy is instant SEQ ID NO: 3, Db is SEQ ID NO:311555 of Krieg:
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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.
Claims 58-60 are rejected under 35 U.S.C. 103 as being unpatentable over Krieg et al. (U.S. Patent No. 10,058,623 Patented 28 Aug 2018).
The teachings of Krieg et al. as applicable to claims 51-53 are described above.
Krieg et al. does not explicitly teach the recited claim limitations of claims 58-60 for the sequences of Krieg et al. cited above.
However, Krieg et al. teaches at least one nucleotide of the oligonucleotide comprises 2’-O methyl, and in some embodiments, each nucleotide of the oligonucleotide comprises a 2’-O-methyl; in some embodiments the oligonucleotide comprises at least one bridged nucleotide which is an LNA nucleotide, cET nucleotide or ENA nucleotide or each nucleotide is an LNA nucleotide (Column 4, lines 48-57); or the single stranded oligonucleotide may consist entirely of bridged nucleotides (Column 16, lines 45-46).
Krieg et al. teach in some embodiments, the single-stranded oligonucleotide comprises modified internucleotide linkages (e.g. phosphorothioate internucleotide linkages, between at least 2, at least 3, at least 4, at least 5, or more nucleotides, or between all nucleotides (Column 5, lines 9-16).
Krieg et al. teach the oligonucleotides of the invention can be stabilized against nucleolytic degradation by the incorporation of a modification, for example nucleic acid sequences of the invention include a phosphorothioate at the first, second or third internucleotide linkage at the 5’ or 3’ end of the nucleotide sequence; another example is a 2’-O-methyl, 2’-O-methoxyethyl modification; the nucleic acid sequence comprise a locked nucleic acid (Column 15, lines 14-32).
Krieg et al. teach pharmaceutical compositions are provided that comprise any of the oligonucleotides disclosed herein and a pharmaceutically acceptable carrier (Column 5, lines 35-38). Krieg et al. teach the pharmaceutical composition can be used in treatment of a disease (Column 15, lines 45-49).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have provided any of the single-stranded oligonucleotides of Krieg et al., including the sequences of SEQ ID NOs: 311552, 311554 or 311555, with a backbone selected from LNA (locked nucleic acid), 2’-O-Me-RNA, 2’-O-methoxyethyl nucleic acids or a combination thereof, and would have been obvious to have provided the single-stranded oligonucleotide with any of the above modifications with one or more phosphorothioate linkages with a reasonable expectation of success. There would be a reasonable expectation of success, because Krieg et al. suggests modifications to any of the single stranded oligonucleotides of the invention with the above recited modifications, and therefore would have amounted to applying a known technique of these chemical modifications to a known product ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to provide the single-stranded oligonucleotides of SEQ ID NOs: 311552, 311554 or 311555, with a backbone selected from LNA (locked nucleic acid), 2’-O-Me-RNA, 2’-O-methoxyethyl nucleic acids, as well as one or more phosphorothioate linkages because Krieg et al. teach the oligonucleotides of the invention can be stabilized against nucleolytic degradation by the incorporation of a modification, for example nucleic acid sequences of the invention include a phosphorothioate at the first, second or third internucleotide linkage at the 5’ or 3’ end of the nucleotide sequence; another example is a 2’-O-methyl, 2’-O-methoxyethyl modification; the nucleic acid sequence comprise a locked nucleic acid (Column 15, lines 14-32).
Accordingly the limitations of claims 58 and 59 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have provided any of the single-stranded oligonucleotides of Krieg et al., including the sequences of SEQ ID NOs: 311552, 311554 or 311555, with a pharmaceutically acceptable carrier to form a pharmaceutical composition with a reasonable expectation of success. There would be a reasonable expectation of success, because Krieg et al. suggests a pharmaceutical composition comprising any of the disclosed oligonucleotides herein and a pharmaceutically acceptable carrier. One of ordinary skill in the art would be motivated to do so because Krieg et al. teach the pharmaceutical composition can be used in treatment of a disease (Column 15, lines 45-49).
Accordingly the limitations of claim 60 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Claims 51-72 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram R 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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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635