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 .
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 specification in Table 1 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
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 and 11-14 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 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 part 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 these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Regarding claim 1, the claim does not describe any specific structure that the claimed ssDNA aptamer must comprise in order to be utilized in a method of treating a subject suffering from a synucleinopathy. Further, the instant specification recites explicit experimentation that must be performed in order to determine if a ssDNA aptamer can be utilized to treat a subject suffering from a synucleinopathy.
The state of the art, the unpredictability of the art, and the relative skill of the ordinary artisan
Regarding the first embodiment of the claim, it is established in the closest prior art that the structure of ssDNA aptamers utilized to treat a subject suffering from a synucleinopathy must comprise a specific structure that is critical for the aptamer’s ability to perform the function and that the claimed genus of aptamers encompasses aptamers that do not perform the claimed function.
Ren (Molecular Therapy Nucleic Acids 17 (2019): 726-740) is directed towards a study concerned with the use of exosomal DNA aptamers that can target α-Synuclein aggregates in order to reduce neuropathological deficits in a mouse model (Abstract). Ren teaches that Parkinson’s disease is the most prevalent form of synucleinopathies that is characterized by the aggregation of an α-Synuclein proteins in neurons (pg. 726). Ren teaches the use of single-stranded DNA aptamers that can bind to a wide range of target proteins (pg. 726). Ren teaches that the administration of exosomes loaded with aptamers to neurons of mice reduce the neuropathological and behavioral deficits in the mouse Parkinson’s disease model (Abstract). Ren teaches that mice that were administered random ssDNA sequences were utilized as a negative control and that the aptamers comprising specific structures were able to improve the performance of mice on a rotarod test (pg. 733; see Figure 6).
Thus, the closest prior art teaches that it is critical that aptamers utilized to treat a subject suffering from a synucleinopathy must comprise a specific structure that can target α-Synuclein aggregates in order to reduce neuropathological deficits. Further, the closest prior art teaches that there are ssDNA aptamers that do not bind to α-Synuclein aggregates and cannot be utilized to treat a subject suffering from a synucleinopathy.
The amount of direction or guidance presented and the amount of experimentation required.
Regarding claim 1, the instant specification does not provide an adequate amount of direction or guidance regarding the treatment of a subject suffering from a synucleinopathy through the use of an ssDNA aptamer that is not limited by structure.
The instant specification teaches that the claimed method was only able to be performed via the use of aptamers that were specifically complementary to a C-terminal truncated form of α-syn were selected from a single-stranded DNA aptamer library using a modified SELEX protocol (i.e., the instant specification teaches that there exist aptamers within the DNA aptamer library that could not be used to perform the claimed method and were not selected by the SELEX protocol) ([0047]). The instant specification teaches the use of a control aptamer, WP40, that had no effect on the accumulation of α-syn when the aptamer was administered to the subject ([0065]). Further, the instant specification only provides support for the usage of specific aptamers that were complementary to α-syn proteins in a singular Parkinson’s disease model (see Example 1). Although the instant specification does explicitly recite that Alzheimer’s disease, dementia with Lewy bodies, and MSA may be treated with the claimed aptamers (see Examples 3-5), no disease models nor subjects suffering from Alzheimer’s disease, dementia with Lewy bodies, or MSA were treated with the claimed aptamers ([0074]-[0076]).
Therefore, as taught in the specification, performing the claimed method to treat a neurological disease via the use of an ssDNA aptamer that is not limited by structure requires experimentation in order to determine if the ssDNA aptamer binds to α-syn in order to treat a subject suffering from a synucleinopathy. Therefore, the instant specification does not provide an adequate amount of direction or guidance regarding the ability of an ssDNA aptamer, not limited by structure, to be utilized to treat a subject suffering from a synucleinopathy.
Accordingly, the amount of experimentation required in order to perform the claimed method in order to treat a subject suffering from a synucleinopathy via the use of an ssDNA aptamer that is not limited by structure is very large in view of the claimed method and the guidance in the instant specification teaching that there are ssDNA aptamers that did not bind to α-syn in order to treat a subject suffering from a synucleinopathy.
Nature of the invention, the presence or absence of working examples, and the breadth of the claims
With regard to claim 1, while Applicant demonstrated that Parkinson’s disease is a synucleinopathy that is caused by the accumulation of insoluble aggregates of α-syn proteins ([0038]) and that the claimed aptamers selected from Apt3, Apt5, Apt7, Apt9, Apt11, Apt15, Apt18, or Apt20 showed high and specific reactivity to α-syn proteins, including high specificity to α-syn 122 seeds ([0061]; see FIG. 1), it is noted that the instant specification also teaches the use of ssDNA aptamers that could not bind to α-syn proteins in order to perform the method as claimed ([0047], [0065]. Further, although Applicant has demonstrated that the claimed ssDNA aptamers that comprise at least one of Apt3, Apt5, Apt7, Apt9, Apt11, Apt15, Apt18, or Apt20 showed high and specific reactivity to α-syn proteins, including high specificity to α-syn 122 seeds, that could be utilized to treat a subject suffering from Parkinson’s disease ([0061]; see FIG. 1, see Example 1), Applicant has not provided any disease models nor subjects suffering from Alzheimer’s disease, dementia with Lewy bodies, or MSA that were treated with the claimed aptamers ([0074]-[0076]; see Examples 3-5).
Because the instant specification does not contain a detailed description of how to make and use the method as claimed, and absent working examples that provide evidence that is reasonably predictive of the ability of a person of ordinary skill in the art to treat a subject suffering from a synucleinopathy via the use of an ssDNA aptamer that is not limited by structure as claimed, the claims are not enabled commensurate in scope with the claimed invention.
Regarding dependent claims 11-14, the claims are dependent on claim 1 and do not rectify the enablement rejection above. Accordingly, claims 11-14 are also rejected under 35 U.S.C. 112(a).
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.
Claim(s) 1, 11, and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ren (Molecular Therapy Nucleic Acids 17 (2019): 726-740).
Regarding claim 1, Ren is directed towards a study concerned with the use of exosomal DNA aptamers that can target α-Synuclein aggregates in order to reduce neuropathological deficits in a mouse model (Abstract). Ren teaches that Parkinson’s disease is the most prevalent form of synucleinopathies that is characterized by the aggregation of an α-Synuclein proteins in neurons (pg. 726). Ren teaches the use of single-stranded DNA aptamers that can bind to a wide range of target proteins (pg. 726). Ren teaches that the administration of exosomes loaded with aptamers to neurons of mice reduce the neuropathological and behavioral deficits in the mouse Parkinson’s disease model (Abstract).
Regarding claim 11, Ren teaches that the synucleinopathy is Parkinson’s disease.
Regarding claim 15, it is noted that the instant specification teaches that the term “pharmaceutically acceptable” refers to a substance that do not cause substantial adverse allergic or immunological reactions when administered to a subject” (Instant specification; [0025]). Therefore, the exosomes comprising the aptamers of Ren are directed towards a composition comprising a pharmaceutically acceptable carrier and an ssDNA aptamer because Ren teaches that the exosomes allow for the efficient delivery of the aptamers to the brain and Ren does not teach that the administration of the exosomes resulted in an adverse allergic or immunological reaction in the mice (pg. 727).
Claim Rejections - 35 USC § 103
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 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.
Claim(s) 12 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ren (Molecular Therapy Nucleic Acids 17 (2019): 726-740).
Regarding claim 12, Ren anticipates claims 1, 11, and 15 as described above.
Ren does not specifically teach that the synucleinopathy comprises dementia with Lewy bodies (Claim 12). Ren does not specifically teach that the synucleinopathy comprises MSA (Claim 14).
However, Ren further teaches that, alongside Parkinson’s disease, multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are species of Parkinson’s diseases that are prevalent forms of the disease (pg. 726). Ren teaches that the diseases are characterized by the abnormal deposition of α-synuclein proteins in the form of aggregates in the neurons of a subject (pg. 726). Ren teaches that there is a need in the art to develop aptamers that can inhibit this aggregation in order to effectively delay or halt the progression of the disease (pg. 726).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the synucleinopathy anticipated by Ren for dementia with Lewy bodies or MSA. A person of ordinary skill in the art would have been motivated to do so in order to inhibit the aggregation of α-synuclein proteins in order to delay or halt the progression of the diseases. A person of ordinary skill in the art would have had a reasonable expectation of success because Ren teaches the use of aptamers that can inhibit the aggregation of α-synuclein proteins in order to treat Parkinson’s disease and further teaches that multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are species of Parkinson’s diseases that are prevalent forms of the disease that are caused by the aggregation of the same α-synuclein proteins.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ren (Molecular Therapy Nucleic Acids 17 (2019): 726-740) as applied to claims 1, 11, and 15 above, and further in view of Uchikado (Journal of Neuropathology & Experimental Neurology 65.7 (2006): 685-697).
Regarding claim 13, Ren anticipates claims 1, 11, and 15 as described above. Ren further teaches that α-synuclein protein aggregates are recruited into Lewy bodies (pg. 731).
Ren does not teach or suggest that the synucleinopathy is Alzheimer’s disease (Claim 13).
However, one of ordinary skill in the art would have considered the teachings of Uchikado as both references are common fields of endeavor pertaining to the study of diseases that result from the aggregation of α-syn proteins in neurons.
Uchikado is directed towards a study concerned with Alzheimer’s disease with amygdala Lewy bodies (Abstract). Uchikado teaches that Alzheimer’s disease is caused by Lewy bodies that are α-synuclein neuronal inclusions (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the synucleinopathy anticipated by Ren for Alzheimer’s disease, as taught by Uchikado. A person of ordinary skill in the art would have been motivated to do so in order to inhibit the aggregation of α-synuclein proteins in order to delay or halt the progression of the disease. A person of ordinary skill in the art would have had a reasonable expectation of success because Ren teaches the use of aptamers that can inhibit the aggregation of α-synuclein proteins in order to treat diseases caused by the aggregation of Lewy bodies while Uchikado teaches that Alzheimer disease is caused by the presence of Lewy bodies in neurons.
Allowable Subject Matter
Regarding the claimed ssDNA aptamers that comprise at least one of Apt3, Apt5, Apt7, Apt9, Apt11, Apt15, Apt18, or Apt20, it is noted that applicant has defined the claimed terms as ssDNA aptamers that comprise specific nucleotide sequences ([0036]; see Table 1 and FIG. 1). It is noted that, per the currently filed sequence listing, the claimed Apt3, Apt5, Apt7, Apt9, Apt11, Apt15, Apt18, and Apt20 correspond to SEQ ID NOs: 1-8.
Applicant demonstrated that Parkinson’s disease is a synucleinopathy that is caused by the accumulation of insoluble aggregates of α-syn proteins ([0038]). Applicant has demonstrated that the aggregation of full length α-syn proteins are promoted by α-syn 122 seeds ([0072]). Applicant has demonstrated that the claimed ssDNA aptamers that comprise at least one of Apt3, Apt5, Apt7, Apt9, Apt11, Apt15, Apt18, or Apt20 showed high and specific reactivity to α-syn proteins, including high specificity to α-syn 122 seeds, that could be utilized to treat a subject suffering from Parkinson’s disease ([0061]; see FIG. 1, see Example 1). Applicant has demonstrated that administering the claimed Apt11 and Apt15 aptamers that were complementary to α-syn 122 seeds significantly decreased the formation of insoluble α-syn proteins in four treated groups ([0066]; see FIG. 4). Thus, Applicant has provided adequate written description report for the use of a composition and method for treating a subject suffering from a synucleinopathy selected from Parkinson’s disease, comprising the step of administering an effective amount of an ssDNA aptamer comprising at least one of the claimed Apt3, Apt5, Apt7, Apt9, Apt11, Apt15, Apt18, or Apt20.
Regarding the closest prior art, Rosa (PG Pub No. US 2004/0123343 A1) is directed towards an invention concerned with polynucleotides useful in the improvement of plants (Abstract). Rosa teaches the use of a nucleotide that comprises a sequence that has 64.0% identity to the claimed SEQ ID NO: 7 ([0005]; see SEQ ID NO: 8999 in attached sequence alignment).
However, neither Rosa nor the prior art teaches or suggests the use of ssDNA aptamers that comprise the claimed Apt3, Apt5, Apt7, Apt9, Apt11, Apt15, Apt18, and Apt20 which correspond to SEQ ID NOs: 1-8 in the currently filed sequence listing.
Accordingly, claims 2-10 and 16 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636