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 .
Claims 1-24 are currently pending. Claims 12-24 are withdrawn as being drawn to a nonelected invention. Claims 1-11 are currently under examination.
Election/Restrictions
Applicant's election of Group I, claims 1-11, drawn to a method from determining a binding score of a nucleic acid to an RNA binding protein by a trained machine learning model, in the reply filed on March 16, 2026 is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the
restriction requirement, the election has been treated as an election without traverse (MPEP §
818.01(a)).
Claims 12-24 are withdrawn from further consideration to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was
made without traverse in the reply filed on March 16, 2026, and is acknowledged.
Information Disclosure Statement
The Information Disclosure Statements filed January 06, 2025; January 06, 2025; May 05, 2025; and January 22, 2026 have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see Page 71, [0287]). 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.
The use of the term HiSeq™, (Page 58, [0232]), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 10 is objected to because of the following informalities:
In claim 10, line 5, “expressing said oligo-library in cells capable of transcribing from said promoter”, should read “expressing said oligo-library in cells that are transcribed from said promoter”.
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.
Claim 7 is 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 7 recites the limitation "said received plurality" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim.
Claim 11 depends from claim 7 and is therefore included in this rejection.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions (i.e., product of nature, a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Every claimed invention must be examined to determine whether the claimed invention complies with 35 U.S.C. 101, particularly whether the claimed invention falls within a 35 U.S.C. 101 judicial exception of non-patentable subject matter (e.g., an abstract idea, law of nature, natural phenomenon, natural product etc.). Phenomena of nature, though just discovered, natural products, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work. See MPEP 2106. As per the “2019 Revised Subject Matter Eligibility Guidance” (Federal Register Vol. 84, No. 4, available 01-07-2019), claims drawn to a process, machine, manufacture or composition of matter are further analyzed according to a two-part process to determine if A) the claim(s) is/are “directed to” a judicial exception because the claims(s) recite(s) a judicial exception (i.e. prong one) that is not integrated into a practical application (i.e. prong two) and, if so, if B) the claim(s) provide(s) an inventive concept, i.e. recite(s) additional elements that amount to significantly more than the judicial exception.
Subject Matter Eligibility Test for Products and Processes
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES
Claims 1-11 are directed to one of the statutory classes. Claims 1-11 are directed to a method comprising receiving, by a trained machine learning (ML) model, one or more variant sequence of a canonical binding motif of an RNA binding protein (RBP) (Process).
Step 2A, Prong One — Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES
Claims 1-11 recite the abstract idea of receiving, organizing and processing data using mathematical concepts. Claims directed to nothing more than abstract ideas, natural phenomena, and laws of nature are not eligible for patent protection (see MPEP 2106.04). Abstract ideas include mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (including procedures for collecting, observing, determining, evaluating, and organizing information (See MPEP 2106.04(a)(2)). In particular, these abstract ideas include:
• A trained machine learning (ML) model, trained to determine a binding score of a sequence to an RBP and determining said binding score for said received one or more variant sequences (Comparing/receiving/organizing data using mathematical concepts such as mathematical formulas/equations, mathematical relationships and mathematical calculations).
• Identifying a binding score associated with each of said variant sequences (Comparing/receiving/organizing data using mathematical concepts such as mathematical formulas/equations, mathematical relationships and mathematical calculations).
• Determining a binding score for each variant sequence of said received plurality and selecting at least one variant sequence of said received plurality with a binding score above a predetermined threshold (mental process, the human mind is capable of
receiving/ collecting data, observing/evaluating, organizing information, mathematical
relationships and mathematical calculations).
• Corelating a relative numerical evaluation of binding of said RBP to said variant sequence inside a cell and a magnitude of said binding score (mental process, the human mind is capable of receiving/ collecting data, observing/evaluating, organizing information, mathematical
relationships and mathematical calculations).
• Detecting expression of said open reading frame and calculating inhibition of expression as compared to expression from said nucleic acid molecule in the absence of said RBP, wherein a magnitude of inhibition is proportional to said binding score. (Comparing/receiving/organizing data using mathematical concepts such as mathematical formulas/equations, mathematical relationships and mathematical calculations).
Therefore, the claims recite elements that constitute one or more judicial exceptions.
Step 2A, Prong Two — Does the Claim Recite an Additional Elements that Integrate the Judicial
Exception into a Practical Application? NO.
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. However, absent are any additional elements recited in the claim beyond the judicial exceptions which integrate the exception into a practical application of the exception. The “integration into a practical application” requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception.
The claim analysis continues with identifying additional elements beyond the judicial exceptions that might evidence integration of the judicial exceptions into a practical application. The steps or elements in addition to the judicial exceptions are: “said binding score of said plurality of variant sequences is determined in an in vivo binding assay comprising expressing in a cell a nucleic acid molecule” and “said binding assay is determined in a high- throughput assay comprising receiving an oligo-library comprising a plurality of nucleic acid molecules each comprising a variant sequences”, which is not indicative of integration into practical application. These steps, recited at a high level of generality, comprise routine data gathering, which is considered an insignificant extra-solution activity. This data gathering is required for using the judicial exceptions. (See MPEP 2106.05(g)). There are no further/additional steps which applies either the identified judicial exception into practical application. Thus, a careful evaluation of the claim as a whole fails to reveal the practical application of the judicial exception to, e.g., effect an improvement to the functioning of a computer or other technology/technical field, effect a particular treatment or prophylaxis for a disease or medical treatment, implement a particular machine that is integral to the claim, or effect a transformation or reduction of a particular article to a different state or thing, or to apply the judicial exception in another meaningful way beyond generally linking its use to a particular technological environment. Accordingly, the claims do not integrate the judicial exception(s) into a practical application and is therefore directed to a judicial exception.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO.
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to “significantly more” than the judicial exception(s) itself. The claims as a whole are analyzed to determine whether any additional element/step, or combination of additional elements/steps, in addition to the identified judicial exception(s) is sufficient to ensure that the claim amounts to “significantly more” than the exception(s).
The eligibility analysis proceeds with identifying any additional elements or limitations, separate from the judicial exceptions, that might potentially render the claims directed to a judicial exception patent eligible. To render the claims patent- eligible, these elements must comprise meaningful limitations that add to or transform the judicial exception to the effect that it amounts to significantly more than the natural correlation or abstract idea itself - i.e. provide an “inventive concept’. The elements that are in addition to the judicial exception comprise: A binding score of said plurality of variant sequences is determined in an in vivo binding assay comprising expressing in a cell a nucleic acid molecule and a binding assay is determined in a high- throughput assay comprising receiving an oligo-library comprising a plurality of nucleic acid molecules each comprising a variant sequences. When considered separately and in combination, these elements do not add significantly more to the judicial exception. These steps are well-understood, routine and conventional activities in the field. For example, Koo et al. (“Inferring Sequence-Structure Preferences of RNA-Binding Proteins with Convolutional Residual Networks”, BioRxiv, 418459, published September 14, 2018), cited on the IDS filed January 06, 2025 and Katz et al. (“An in Vivo Binding Assay for RNA-Binding Proteins Based on Repression of a Reporter Gene”, ACS Synthetic Biology, 7(12), published November 08, 2018, cited on the IDS filed January 06, 2025 discloses A binding score of said plurality of variant sequences is determined in an in vivo binding assay comprising expressing in a cell a nucleic acid molecule and a binding assay is determined in a high- throughput assay comprising receiving an oligo-library comprising a plurality of nucleic acid molecules each comprising a variant sequences. The claims recite an abstract idea with additional elements. Because these elements are not inventive concepts, the claims do not integrate the abstract idea into a practical application. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). The claims therefore do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Accordingly, the claims do not qualify as patent-eligible subject matter.
For further information, please see the latest revision of MPEP 2104-2106 {Patent Subject Matter Eligibility Under 35 U.S.C. 101}, including MPEP 2106.04 {Eligibility Step 2A: Whether a Claim is Directed to a Judicial Exception} and 2106.05 {Eligibility Step 2B: Whether a Claim Amounts to Significantly More}, as well as the guidance on Subject Matter Eligibility, including the 2019 Guidance issued Jan. 7, 2019, and the October 2019 Update, provided on the USPTO website at https:/Awww.uspto.gov/patent/laws-and-regulations/examination-policy/subject-matter- eligibility.
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 1-4, 6-8 and 11 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Koo et al. (“Inferring Sequence-Structure Preferences of RNA-Binding Proteins with Convolutional Residual Networks”, BioRxiv, 418459, published September 14, 2018), cited on the IDS filed January 06, 2025.
Regarding claim 1, Koo teaches a method comprising receiving, by a trained machine learning (ML) model, one or more variant sequence of a canonical binding motif of an RNA binding protein (RBP) (Abstract, Page 2, First Paragraph, Page 3, Fourth Paragraph, Page 4, First—Second Paragraph, Page 5, Third Paragraph, Page 8, Second Paragraph, Page 12, Last Paragraph and Figs. 3-4). Koo teaches said ML model is trained to determine a binding score of a sequence to said RBP and determining said binding score for said received one or more variant sequences (Page 2, Fourth Paragraph, Page 3, First Paragraph—Page 4, Second Paragraph, Page 6, First Paragraph and Figs. 2-3).
Regarding claim 2, Koo teaches said trained ML model is produced by a method comprising at a training stage, training a machine learning model on a training set (Page 13, Last Paragraph). Koo teaches a plurality of variant sequences of said canonical binding motif of said RBP, wherein each variant comprises at least one nucleotide change from said canonical binding motif (Page 12, Second—Fifth Paragraph). Koo teaches labels identifying a binding score associated with each of said variant sequences (Page 4, First Paragraph and Page 12, Second—Fifth Paragraph).
Regarding claim 3, Koo teaches said received one or more variant sequence comprises at least five nucleotide changes from said canonical binding motif (Page 5, Third Paragraph and Fig. 3).
Regarding claim 4, Koo teaches said received one or more variant sequences comprises a different number of nucleotides than said canonical binding motif (Page 12, Second Paragraph).
Regarding claim 6, Koo teaches said plurality of variant sequences of a canonical binding motif of an RBP comprises at least 10000 different variant sequences (Page 5, Third Paragraph, Page 12, Last Paragraph—Page 13, Fifth Paragraph and Fig. 3).
Regarding claim 7, Koo teaches receiving by said trained ML model a plurality of variant sequences, determining a binding score for each variant sequence of said received plurality and selecting at least one variant sequence of said received plurality with a binding score above a predetermined threshold (Page 12, Second—Fifth Paragraph, Page 13, Sixth—Eighth Paragraph and Figs. 3-4).
Regarding claim 8, Koo teaches said binding score is a relative numerical evaluation of binding of said RBP to said variant sequence inside a cell and wherein a magnitude of said binding score correlates to a magnitude of binding (Page 6, Fourth Paragraph).
Regarding claim 11, Koo teaches generating a synthetic nucleic acid sequence synthetic nucleic acid molecule or both comprising said selected at least one variant sequence with a binding score above a predetermined threshold (Page 5, Third Paragraph, Page 6, Fifth Paragraph, Page 9, Second—Third Paragraph, Page 10, First Paragraph, Page 12, Second—Fifth Paragraph, Page 13, Fifth—Eighth Paragraph and Figs. 3-4 and 7).
Koo teaches each and every limitation of claims 1-4, 6-8 and 11, therefore Koo anticipates claims 1-4, 6-8 and 11.
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 5 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Koo et al. (“Inferring Sequence-Structure Preferences of RNA-Binding Proteins with Convolutional Residual Networks”, BioRxiv, 418459, published September 14, 2018), cited on the IDS filed January 06, 2025, as applied to claims 1-4, 6-8 and 11 above, in view of Katz et al. (“An in Vivo Binding Assay for RNA-Binding Proteins Based on Repression of a Reporter Gene”, ACS Synthetic Biology, 7(12), published November 08, 2018, cited on the IDS filed January 06, 2025.
Regarding claim 5, Koo teaches the RBP as discussed above.
Regarding claim 9, Koo teaches said binding score of said plurality of variant sequences is determined in an in vivo binding assay (Page 1, Second Paragraph, Introduction and Page 3, Fourth Paragraph). Koo teaches a variant sequence of said canonical binding motif as discussed above. Koo teaches expressing in said cell said RBP as discussed above.
Regarding claim 10, Koo teaches a variant sequences of said plurality of said canonical binding motif as discussed above.
Koo does not teach or suggest the RBP is a phage coat protein, optionally wherein said phage coat protein is selected from PCP, QCP and MCP. Koo does not teach or suggest expressing in a cell a nucleic acid molecule comprising a promoter and a variant sequence of said canonical binding motif operatively linked to an open reading frame. Koo does not teach or suggest detecting expression of said open reading frame and calculating inhibition of expression as compared to expression from said nucleic acid molecule in the absence of said RBP, wherein a magnitude of inhibition is proportional to said binding score. Koo does not teach or suggest said binding assay is determined in a high-throughput assay comprising receiving an oligo-library comprising a plurality of nucleic acid molecules each comprising a variant sequences of said plurality of said canonical binding motif inserted 3' to a promoter operably linked to an open reading frame encoding a fluorescent molecule and 5' to said open reading frame. Koo does not teach or suggest expressing said oligo-library in cells capable of transcribing from said promoter, sorting said cells by fluorescence and determining a sequence of said variant sequence in said sorted cells.
Katz teaches a binding score of said plurality of variant sequences is determined in an in vivo binding assay (Abstract, Page 2766, Left Column, First Paragraph and Right Column First Paragraph and Fig. 3). Katz teaches the RBP is a phage coat protein and said phage coat protein is selected from PCP, QCP and MCP (Abstract, Page 2766, Left Column, First Paragraph and Right Column First Paragraph). Katz teaches expressing in a cell a nucleic acid molecule comprising a promoter and a variant sequence of said canonical binding motif operatively linked to an open reading frame (Page 2766, Right Column, First Paragraph and Fig. 1). Katz teaches expressing in said cell said RBP (Page 2766, Right Column, First Paragraph and Fig. 1). Katz teaches detecting expression of said open reading frame and calculating inhibition of expression as compared to expression from said nucleic acid molecule in the absence of said RBP, wherein a magnitude of inhibition is proportional to said binding score (Page 2766, Left Column, First Paragraph and Right Column First Paragraph and Figs. 1-2). Katz teaches binding assay is determined in a high-throughput assay comprising receiving an oligo-library comprising a plurality of nucleic acid molecules each comprising a variant sequences of said plurality of said canonical binding motif inserted 3' to a promoter operably linked to an open reading frame encoding a fluorescent molecule and 5' to said open reading frame (Abstract, Page 2766, Left Column, First Paragraph, Page 2767, Left Column First Paragraph—Right Column, First Paragraph, Page 2769, Right Column, Last Paragraph, Page 2770, Left Column, Last Paragraph and Fig. 1). Katz teaches expressing said oligo-library in cells capable of transcribing from said promoter, sorting said cells by fluorescence and determining a sequence of said variant sequence in said sorted cells (Abstract, Page 2766, Left Column, First Paragraph—Right Column, First Paragraph, Page 2767, Left Column First Paragraph—Right Column, First Paragraph, Page 2769, Right Column, Last Paragraph, Page 2770, Left Column, Last Paragraph and Fig. 1-3). Katz teaches using the disclosed synthetic regulatory circuit as a binding assay, allows for quantitatively characterizing RBP binding affinity to a set of mutated binding sites in a high-throughput manner, increasing the understanding of RBP-RNA binding in vivo and enabling the engineering of more complex RNA-based applications (Page 2766, Left Column First Paragraph).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to modify the teachings of Koo with the teachings of Katz, to use a binding score of said plurality of variant sequences is determined in an in vivo binding assay where the RBP is a phage coat protein and said phage coat protein is selected from PCP, QCP and MCP. This allows for quantitatively characterizing RBP binding affinity to a set of mutated binding sites in a high-throughput manner, increasing the understanding of RBP-RNA binding in vivo and enabling the engineering of more complex RNA-based applications as taught by Katz (Page 2766, Left Column First Paragraph).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA DANIELLE PARISI whose telephone number is (571)272-8025. The examiner can normally be reached Mon - Friday 7:30-5:00 Eastern with alternate Fridays off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at 571-272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JESSICA D PARISI/ Examiner, Art Unit 1684
/HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684
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