DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of an oligomer of SEQ ID NO:1887 in the reply filed on 09/12/2025 is acknowledged.
Claims Status
Claims 1-111 is/are cancelled and claims 112-145 is/are newly added. Claims 112-145 is/are currently pending. Claims 112-145 is/are under examination.
Information Disclosure Statement
The information disclosure statement filed 06/30/2022 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein which has been struck through has not been considered. NPL 322 (Monti 2007) was not provided; however, a different reference by Monti (Neurotox Res (2010) 17:130-141) was provided with the IDS filed 12/10/2020 in the parent application 16759698. NPL 343 (Xu 2003) was not provided; however, a different reference by Xu (Brain Res (2007) 1139:220-225) was provided with the IDS filed 12/10/2020 in the parent application 16759698.
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 136-145 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.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed methods of claims 138-139, 141, 143, and 145 is that administration of the claimed oligonucleotide to a subject can treat or prevent any disease associated with SNCA, including neurodegenerative diseases such as Parkinson’s disease, dementia with Lewy bodies, diffuse Lewy body disease, pure autonomic failure, multiple system atrophy, neuronopathic Gaucher’s disease, and Alzheimer’s disease. The broadest reasonable interpretation of the claimed methods of claims 140, 142, and 144 is that they encompass methods comprising a step of administering the claimed oligonucleotides to a subject, these having the intended use of treating any neurodegenerative disease, as detailed in the specification (page 2: encompassed are methods of reducing the amount of alpha-synuclein protein in a cell or animal having a neurodegenerative disease and methods for ameliorating at least one symptom or hallmark of a neurodegenerative disease). A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification teaches that a disease associated with SNCA can be treated by administering a therapeutically effective amount of a pharmaceutical composition comprising the claimed oligonucleotide (page 17). The art at the time of filing taught that transgenic models, including mouse models, are not proven to have therapeutic predictive validity for human treatment (see Koprich, 2017, full document, including Table 2, a summary of benefits and problems associated with different models of α-synucleinopathy). Koprich teaches, in Figure 2, that in order to validate preclinical efficacy of an α-synucleinopathy therapeutic, the therapeutic should be tested in multiple transgenic rodent models, then in a transgenic non-human primate model, wherein testing in the rodent models should show improvement in striatal dopamine measures, striatal DAT, nigral TH+ cell numbers, and behavioral measures, and testing in non-human primate models should show improvements in striatal dopamine, striatal DAT, nigral TH+ cell numbers, and α-synuclein levels (Fig. 2). Koprich also teaches, in Figure 2, that after preclinical validation, the therapeutic can be considered for further clinical development. Based on the teachings of the prior art regarding the unpredictability of transgenic mouse models in predicting therapeutic efficacy of a pharmaceutical composition in the treatment of SNCA-associated diseases, an artisan would not be able to predict based on rodent model data that a particular therapeutic could be used to treat an SNCA-associated disease. The specification as filed does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses administration of the claimed oligonucleotide to a mouse model (wildtype B6C3F1 mice with pre-formed fibrils administered to the mouse striatum; and SNCA PAC transgenic mice) resulting in clearance of fibrils (pages 185-186, 190-191). The specification also teaches administration of the claimed oligonucleotide to non-human primates (cynomolgus monkeys), resulting in decrease in SNCA mRNA (page 187), but the specification does not teach that synuclein fibril aggregates were cleared in the non-human primate model, nor that any symptoms associated with an SNCA-associated disease were alleviated. An artisan would not be able to determine that the models as described were predictive of treatment of the modeled diseases.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is treatment of any disease associated with SNCA, a person having ordinary skill in the art would have to perform multiple further experiments in human clinical trials or in animal models predictive of treatment of a representative number of diseases associated with SNCA, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, Claims 136-145 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Allowable Subject Matter
Claims 112-135 are allowed.
The following is a statement of reasons for the indication of allowable subject matter:
The closest prior art is US20140005252A1 (Bennett; cited by applicant with IDS filed 06/30/2022). Bennett teaches a modified oligonucleotide consisting of 12-30 linked nucleotides (claim 1), all of which oligonucleotides consist of sequences found in SEQ ID NO:2 (paragraph [0288]), wherein SEQ ID NO:2 of Bennett comprises the sequence of instant SEQ ID NO:1887 (see alignment below).
PNG
media_image1.png
154
658
media_image1.png
Greyscale
However, none of the oligonucleotides taught in Bennett have the sequence of instant SEQ ID NO:1887. Table 2 of Bennett teaches the oligonucleotide sequences tested by Bennett, and teaches that different oligonucleotides targeting different regions of the SNCA mRNA result in vastly different SNCA inhibition, ranging from 0% inhibition to 92% inhibition (see Table 2, “% inhibition” column). Moreover, the NCBI Clinical Variant (ClinVar) information available for the SNCA gene does not show that any known variants of the SNCA gene are known in or near the segment of the SNCA gene targeted by the instant oligonucleotide (see provided table of ClinVar results), and the prior art (see Touchman, 2001) teaches that the region of the SNCA gene targeted by the claimed oligonucleotide is within a intron but not at an intron-exon boundary (see Table 1: SEQ ID NO:1887 is identical to the region from 53672-53653 of AF163864.1, see alignment below, corresponding to intron 4 of SNCA as shown in Touchman).
PNG
media_image2.png
227
870
media_image2.png
Greyscale
Nucleotides 53672-53653 of SNCA, and the approximately 6,000 nucleotides upstream and 5,000 nucleotides downstream of this region, are not shown by Touchman to be evolutionarily conserved (see Fig. 2). An artisan would not be able to assume that an oligonucleotide of any sequence targeting the SNCA mRNA would be able to inhibit expression of SNCA, nor would an artisan have a reason to target nucleotides ~47,500-58,500 of the SNCA gene. Furthermore, Bennett teaches oligonucleotides wherein all linkages are phosphorothioate linkages (paragraph [0304]; claim 15). The oligonucleotide recited in the instant claims comprise a phosphorothioate linkage pattern of SOOOSSSSSSSSSSSOOSS (S=phosphorothioate, O=phosphodiester). Bennett does not teach that the 3’ and 5’ wings of the gapmer comprise a mix of phosphorothioate and phosphodiester linkages. It would not be obvious to an artisan, based on the teachings of Bennett, that a gapmer of SEQ ID NO:1887 comprising the phosphorothioate linkage pattern SOOOSSSSSSSSSSSOOSS should be made.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM 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, Ram Shukla can be reached on (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
For those applications where applicant wishes to communicate with the examiner via Internet communications, e.g., email or video conferencing tools, the following is a sample authorization form which may be used by applicant:
"Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file."
To facilitate processing of the internet communication authorization or withdraw of authorization, the Office strongly encourages use of Form PTO/SB/439, available at www.uspto.gov/patent/patents-forms. The form may be filed via EFS-Web using the document description Internet Communications Authorized or Internet Communications Authorization Withdrawn to facilitate processing. See MPEP 502.03(II).
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AFRICA M MCLEOD/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635