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 .
It appears the inventor(s) filed the current application pro se (i.e., without the benefit of representation by a registered patent practitioner). While inventors named as applicants in a patent application may prosecute the application pro se, lack of familiarity with patent examination practice and procedure may result in missed opportunities in obtaining optimal protection for the invention disclosed. The inventor(s) may wish to secure the services of a registered patent practitioner to prosecute the application, because the value of a patent is largely dependent upon skilled preparation and prosecution. The Office cannot aid in selecting a patent practitioner.
A listing of registered patent practitioners is available at https://oedci.uspto.gov/OEDCI/. Applicants may also obtain a list of registered patent practitioners located in their area by writing to Mail Stop OED, Director of the U.S. Patent and Trademark Office, P.O. Box 1450, Alexandria, VA 22313-1450.
In addition, Applicant is encouraged to contact the Application Assistance Unit (AAU), which unit can provide assistance with a broad range of questions and issues. The AAU is available Monday through Friday from 8:30 AM to 5:00 PM (Eastern). The AAU contact information is the following: 888-786-0101 (Toll Free) or 571- 272-4000 (Local).
Application Status
Receipt is acknowledged of amendment, filed 06/05/2025.
It is noted that the amendment to the claims filed on 06/05/2025 does not comply with the requirements of 37 CFR 1.121(c) because the election filed was not signed by the inventor. However, in the interest of compact prosecution, the amendment to the claims has been entered.
The numbering of claims is not in accordance with 37 CFR 1.126 which requires claims to be numbered consecutively. For the purpose of examination, misnumbered claims have been renumbered as the original claim numbers. In response to this office action, Applicant is required to submit amended claims with claims 1-56 renumbered as claims 2-4, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 30, 32, 33, 35, 36, 38, 39, 41, 42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 68, 69, 71, 72, 74, 75, 77, 78, 80, 81, 83, 84, 86, 88 and 93. The amendment is required to maintain the integrity of the electronic file.
Claims 2-4, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 30, 32, 33, 35, 36, 38, 39, 41, 42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 68, 69, 71, 72, 74, 75, 77, 78, 80, 81, 83, 84, 86, 88 and 93 are currently pending.
Election/Restriction
During a telephone conversation with Mohammad Heidaran on 08/28/2025 a provisional election was made with traverse to prosecute the invention of Group I, claims 1-88 and 90-93 as well as the species election of SEQ ID NO: 4 for the guide RNA and SEQ ID NO: 3 (rs9310709) for the SNP. Affirmation of this election must be made by applicant in replying to this Office action. Claims 1, 5-11, 13, 16, 19, 22, 25, 28, 29, 31, 34, 37, 40, 43, 46, 49, 52, 55, 58, 61, 64, 67, 70, 73, 76, 79, 82, 85, 87 and 90-92 are cancelled by Applicant.
Claim 89 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 15, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81 and 84 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
The species election of the SNP identified as rs9310709 (SEQ ID NO: 3) has been found free of the art, however in order to determine the patentability of the claims, the search has been extended to the next species which is considered to be “other SNPs discovered to be positively correlated with severe mental health diseases” specifically rs362307. This SNP is taught by prior art (Aronin et al US 8987222 B2) as being positively correlated with Huntington’s Disease (Column 57, Lines 59-60).
The species election for the gRNA identified as SEQ ID NO: 4 has been withdrawn.
Claims 2-4, 12, 14, 17, 18, 20, 23, 26, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86, 88 and 93 are currently under examination.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”
In the current case, the view numbers for Figures 1 and 3-5 are preceded by the word "Figure" instead of the abbreviation "FIG.".
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
Page 2, Paragraph 2 states “Foe example” instead of “For example”.
Page 2, Paragraph 5 states “sever” instead of “severe”
Appropriate correction is required.
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 Pages 6, 7 and 12. This objection may be overcome by amending the specification to delete “http” and “https.”
The disclosure is objected to because it references tables contained in an excel spreadsheet as “megatables”, however, the tables are 50 pages or less and multiple tables contained within the “megatables” is 100 pages or less. The tables must be submitted as part of the specification pages. See MPEP § 608.05(b).
Claim Objections
Claims 2, 3, 4, 12, 14, 15, 17, 18, 20, 23, 26, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86 and 93 are objected to because of the following informalities:
Claims 4 and 12 are objected for the form of the full sequences within the claims. It would be remedial to amend the claim to recite the sequence followed by the sequence identifier in parenthesis, such as (gattat…(SEQ ID NO:1)).
Claims 2, 4, 12, 14, 15, 17, 18, 20, 23, 26, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86 and 93 do not end in a period. MPEP 608.01(m) states, “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations”.
Claims 2, 4, 12 contain periods within the claim. MPEP 608.01(m) states, “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations”.
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 2, 3, 4, 12, 14, 15, 17, 18, 20, 23, 26, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86, 88 and 93 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.
Claims 2, 12 and 14 recites the limitation "Excel document 1" in lines 1, 2 and 3, respectively. MPEP 2173.05(s) states "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted)." There is insufficient antecedent basis for this limitation in the claim.
Claim 93 is rejected as failing to define the invention in the manner required by 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
The claim(s) are narrative in form and replete with indefinite language. The structure which goes to make up the invention must be clearly and positively specified. The structure must be organized and correlated in such a manner as to present a complete operative device. The claim(s) must be in one sentence form only. Note the format of the claims in the patent(s) cited.
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 2-4, 12, 14, 17, 18, 20, 23, 26, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86, 88 and 93 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 the treatment of Huntington’s Disease (HD), comprising administering to a patient with a mutant huntingtin (htt) mNRA an effective amount of a first RNA silencing agent targeting a HD-associated single nucleotide polymorphism (SNP) in combination with one or more RNA silencing agents targeting one or more other htt SNPS, such that NRA silencing of said htt mRNA occurs, wherein the at least one htt SNP is the U isoform of rs362307, and wherein at least tone other htt SNP has a frequency of heterozygosity of at least 20% or more in an HD patient population, does not reasonably provide enablement for treating any other severe mental health disease by targeting any other SNPs, including any SNP discovered to be positively correlated with severe mental health diseases, or by targeting the specifically listed SNP, such as elected rs9310709, or for treatment that uses a gRNA and Cas9 protein, within a CRISPR system, in order to treat any severe mental health disease. The methods of treating enabled by the prior art, such as the method of treating Huntington's disease of Aronin et al (US Patent No. 8,987,222 B2; However, this embodiment does not find support in the current disclosure). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The claims are drawn to a method for treating any severe mental disease by targeting single nucleotide polymorphisms. The method comprises the use of a Cas9 protein and gRNA CRISPR complex system. The nature of the invention is complex in that the targeting of a SNP must result in a therapeutic outcome.
Breadth of the claims: The claims broadly encompass any severe mental health disease being treated via any method of targeting a SNP, including the use of any CRISPR cas genome editing system. Claim 2 recites, “Method of treatment by targeting 1 or more SNPs outlined in Excel document I of this application and herein and any other SNP discovered to be positively correlated with severe mental health disease”. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification envisions the modification of specific target SNPs using nonviral LNP-mediated CRISPR-Cas9 mRNA-based strategy for in vivo brain specific genome editing (Page 2, Paragraph 3). The specification envisions treating severe mental illness but does not specify what mental illnesses the therapy should be capable of treating (Page 2, Paragraph 7).
The specification does not include specific guidance or a working example of how a SNP is targeted to successfully treat any severe mental health disease. The specification states “Currently there are no curative option for mental diseases” (Page 2, Paragraph 6). The specification continues to state “The efficiency of this mutation is largely dependent on the specificity and sequence of gRNA and activity of Cas9 endonuclease. It is also expected that LNP complex to have some off target effects which is defined as changes in DNA outside of target SNP which may or may not be consequential.” (Page 4, 1st full paragraph). The specification envisions a composition comprising a lipid nanoparticle comprising a Cas9 protein and guide RNA complex, comprising a promoter, target sequence and guide RNA, wherein it is delivered to a subject brain via intrathecal delivery and/or delivery to cerebrospinal fluid (Page 9, Paragraph 2). The specification provides no description or working examples of successful use or administration to a subject where successful treatment of a severe mental health disease would occur.
Predictability and state of the art: For some relevant background, Amare et al (EPMA Journal 8:211-227, 2018) teaches that so far, the progress of uncovering single nucleotide polymorphisms (SNPs) underpinning treatment efficacy in mood disorders (e.g., SNPs associated with selective serotonin re-uptake inhibitors or lithium treatment response in patients with bipolar disorder and major depressive disorder) are encouraging, but not adequate (Page 211, Abstract). Amare teaches that the causes of mood disorders are complex and involve the interplay between genetic predisposition and non-genetic biological, psychological, and social factors (Page 212, Column 1). Amare teaches that with the successful completion of the Human Genome Project that there is an expectation that pharmacological treatment response and treatment-associated side effects would become more predictable from patient’s genetic signatures, however, that is not yet possible (Page 212, Column 1).
However, as taught by Ayoub et al (British Journal of General Practice 72:721, pgs. 396-398; 2022), the GWAS provides a measure of SNPs associated with disease - they do not prove causation but rather correlation (Page 397, Column 3). Ayoub teaches that understanding of the role SNPs play in common complex disease is evolving and scores may not adequately reflect potential gene- environment interactions and epigenetic modifications (changes in gene expression) that may impact disease risk (Page 397, Column 3). Thus, meaning that even though the human genome is known does not mean that it is possible to treat complex diseases by targeting the SNPs within those genes associated with severe mental health disease.
Kurishev et al (J. Mol. Sci. 2023, 24, 241, pgs. 1-22) teaches that major psychiatric disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), depression, and schizophrenia (SZ), are characterized by complex etiopathogenetic mechanisms involving neuroanatomic abnormalities, biochemical imbalances, genetic and epigenetic changes (Page 2, Paragraph 1). Kurishev teaches it is important to note that the pathophysiology, of major psychiatric disorders, is multideterministic as environmental factors interact with the polygenic architecture and even the physiological status of the patient influences the symptoms and signs of the diagnosed disorder; thus, the pathogenesis of psychiatric disorders can be considered a dynamic process with limited knowledge about spatial and temporal characteristics of the brain (Page 2, Paragraph 1). Kurishev envisions using CRISPR-cas strategies to manipulate genome architecture, genome sequence, and epigenomes for treating mental disorders, however, Kurishev does not teach the success of the CRISPR-cas strategies (Page 17, Paragraph 2).
In the context of a specific severe mental health disease, such as Huntington’s disease, Aronin et al (US 8,987,222 B2) teaches rs362307 was significantly associated with Huntington’s Disease (Column 57, Lines 59-60). Aronin teaches that targeted reduction of mutant Huntingtin mRNA is considered an ideal strategy for treating HD (Column 63, Lines 4-5). Aronin teaches that in the event that the mutant htt allele is more abundant than the wild type htt allele in cells of HD patients, indiscriminate silencing could in theory eliminate the wild type htt allele while preserving the mutant htt allele, thereby actually exacerbating the disease (Column 63, Lines 50-54). Aronin teaches a method of silencing mutant huntingtin (htt) mRNA in a HD patient population, comprising administering to said patient population an effective amount of a first RNA silencing agent targeting a HD-associated htt single nucleotide polymorphism (SNP) in combination with one or more RNA silencing agents targeting one or more other htt SNPs, such that RNA silencing of said mRNA occurs, wherein the HD-associated htt SNP is the U isoform of rs362307, and wherein at least one other htt SNP has a frequency of heterozygosity of at least 20% or more in a sample population (Page 118, Claim 1).
Although possible to use SNPs as a treatment for Huntington’s disease, there is no predictability that a Cas9 and gRNA can be used to successfully treat any severe mental health disease. In the instant case, the claims encompass the use of the Cas9 protein and guide RNA for a method of targeting SNPs for treatment of severe mental health diseases, without the exact function or specific mental health disease defined in order to replicate with certainty the same results provided in the claimed invention.
Amount of experimentation necessary: In order to practice the claimed invention, an immense amount of experimentation would be required. As discussed above, the specification itself provides only that the system can be used to treat severe mental health diseases. The specification does teach how the system works in treating severe mental health diseases or if it is actually successful in treating a specific severe mental health disease. Therefore, experiments could be conducted, but in view of the specification there does not appear to be any amount of experiment that would be sufficient to reliably produce the exact product of the invention. Such experimentation would not be possible due to not having the definition, steps or function of the system in treating or successfully treating any severe mental health disease. Therefore, it would require immense amount of unpredictable experimentation to practice the claimed invention with such variants in the possible result.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 2-4, 12, 14, 17, 18, 20, 23, 26, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86, 88 and 93 are not considered to be fully enabled by the instant disclosure.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2, 3 and 93 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Aronin et al (US 8,987,222 B2).
For the purposes of this rejection, claim 93 is being interpreted as being drawn to a method comprising targeting a SNP, rs362307, using RNA silencing agents for the purpose of treating Huntington’s Disease.
Regarding claims 2, 3 and 93, Aronin teaches rs362307 was significantly associated with Huntington’s Disease (Column 57, Lines 59-60). Aronin teaches that targeted reduction of mutant Huntingtin mRNA is considered an ideal strategy for treating HD (Column 63, Lines 4-5). Aronin teaches that in the event that the mutant htt allele is more abundant than the wild type htt allele in cells of HD patients, indiscriminate silencing could in theory eliminate the wild type htt allele while preserving the mutant htt allele, thereby actually exacerbating the disease (Column 63, Lines 50-54). Aronin teaches a method of silencing mutant huntingtin (htt) mRNA in a HD patient population, comprising administering to said patient population an effective amount of a first RNA silencing agent targeting a HD-associated htt single nucleotide polymorphism (SNP) in combination with one or more RNA silencing agents targeting one or more other htt SNPs, such that RNA silencing of said mRNA occurs, wherein the HD-associated htt SNP is the U isoform of rs362307, and wherein at least one other htt SNP has a frequency of heterozygosity of at least 20% or more in a sample population (Page 118, Claim 1).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm 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, JENNIFER A DUNSTON can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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.
/ALEXANDRA ROSE LIPPOLIS/ Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637