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 Requirement
Applicant’s election without traverse of Species B (claim 4) in the reply filed on 07/21/2026 is acknowledged. Claim 3 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/21/2026.
Claim Status
Claims 6-8, 12-13, 18, 20-21, 23-24, 26-31, 37-76 and 81 are cancelled by Applicant.
Claims 1-5, 9-11, 14-17, 19, 22, 25, 32-36 and 77-80 are currently pending.
Claim 3 is withdrawn, as discussed above in Election Requirement.
Claims 1-2, 4-5, 9-11, 14-17, 19, 22, 25, 32-36 and 77-80 are under examination.
Claims 1-2, 4-5, 9-11, 14-17, 19, 22, 25, 32-36 and 77-80 are rejected.
Claims 2, 19, 22, 25, 36 and 79 are objected to.
Priority
The instant application claims priority to international application No. PCT/US2021/031302, filed on May 7, 2021, which claims priority to U.S. Provisional Application No. 63/021,345, filed May 7, 2020. The claims to priority are acknowledged. As such, the effective filing date for claims 1-2, 4-5, 9-11, 14-17, 19, 22, 25, 32-36 and 77-80 is May 7, 2020.
Information Disclosure Statement
The IDSs filed 9/15/2023, 4/11/2025, 6/3/2025, 8/6/2025 and 11/20/2025 follow the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of the list of references cited from these IDSs is included with this Office Action.
Drawings
The drawings are objected as failing to comply with 37 CFR 1.84(u)(1) because the view numbers recite “Figure 1”, “Figure 2A”, etc. The figures should instead recite “FIG. 1”, “FIG. 2A”, etc.
The drawings are objected to because in FIG 6 it appears that the numbers 8-12 are mislabeled as 1-5 after number 7.
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.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. In paragraph [2] of the specification the name of the file is “MRT-2131WO_SL” whereas the name of the file in the Sequence Listing is “MRT-2131WO”, and the size is in KB rather than bytes.
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 incorporation-by-reference paragraph, 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Paragraphs [108] and [158] contain hyperlinks. 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.
Abstract
The abstract of the disclosure is objected to because line 1 should recite “for generating an”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 2, 19, 22, 25, 36 and 79 are objected to because of the following informalities:
Claim 2, lines 2-3, appears that it should recite “acid [[and]] removed”.
Claim 19, line 8, should recite “cytosine; and”.
Claim 22, line 8, should recite “1; and”.
Claim 25, lines 4-5, should recite “determining whether any optimized nucleotide … sequences, contain at least 2”.
Claim 36, line 2, should be indented to the same degree as line 4.
Claim 79, line 4, should recite GAAGAGC; and UCUAGA.”
Appropriate correction is required.
Claim Interpretation
35 USC 112(f)
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claim 33 recites a data processing system comprising means for carrying out the method of claim 1. The data processing system is interpreted as a computer-implemented means-plus-function limitation which requires the structure to be hardware and algorithms to perform the claimed function. Below are the hardware and algorithms found in the specification for steps i-v in claim 1 performed by the data processing system of claim 33.
MPEP 2181.II.A recites receiving data is a coextensive function of a processor. As such, the structure for performing claim 1, steps i-ii, is a processor.
Step iii does not have an associated structure in the specification. Specification paras. [11], [111], [117-118], [232] and [260] reiterate the claimed function, which is not sufficient structure. MPEP 2181.II.B recites “simply reciting the claimed function in the specification will not be a sufficient disclosure for an algorithm which, by definition, must contain a sequence of steps.”
Step iv has recited algorithms in the specification, for example, in para. [12]. These algorithms, and equivalents thereof, will be interpreted as the structure for step iv.
Step v has recited algorithms in the specification, for example, in para. [13]. These algorithms, and equivalents thereof, will be interpreted as the structure for step iv.
Claim Rejections - 35 USC § 112
35 USC 112(a)
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 33 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 33 fails to comply with the written description requirement because it does not adequately link or associate adequately described particular structure, material, or acts to perform the functions recited in the claim identified to invoke 35 U.S.C. 112(f) or pre- AIA 35 U.S.C. 112, sixth paragraph. As discussed in Claim Interpretation, claim 33 recites a data processing system that invokes 35 U.S.C. 112(f). Neither the specification nor the drawings clearly associate hardware or sufficient algorithms to perform all the claimed functions. Although the specification provides hardware and algorithms for the data processing system to perform steps i-ii and iv-v of claim 1, MPEP 2181.II.B recites “[w]hen the specification discloses an algorithm that only accomplishes one of multiple identifiable functions performed by a means-plus-function limitation, the specification is treated as if it disclosed no algorithm.” Thus, in accordance with MPEP 2181.IV, the disclosure does not provide written description support for the data processing system.
35 USC 112(b)
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 4-5, 9-11, 14-17, 19, 22, 25, 33, 36 and 77-80 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 dependent from a rejected claim are also rejected, unless otherwise noted.
Claim 4 recites “the usage frequency of the removed codons ... the remaining codons … the usage frequency of each remaining codon”. It’s unclear which amino acid this recitation refers because claim 2 performs step (a) for each amino acid, resulting in each amino acid having removed and remaining codons. Clarify which amino acid the recitation refers to in claim 2.
Claim 5, step b, recites “the probability” which lacks antecedent basis. It is recommended to change to “a probability”.
Claim 5, lines 5 and 7, recite “the first amino acid”. It’s unclear which first amino acid is referenced because claim 5, step a, recites “the one or more codons associated with a first amino acid” and claim 2, step a, recites “each codon associated with a first amino acid removed in step (iii).” Clarify which first amino acid is referenced.
Claim 9 recites “the list of optimized nucleotide sequences” which lacks antecedent basis. Provide antecedent basis or clarify to what the recitation refers.
Claims 10 (lines 3-4), claim 14 (lines 4-5), claim 19 (line 6), claim 22 (lines 5-6), and claim 25 (lines 4-5) recite “in the … most recently updated list, of optimized nucleotide sequences” which lacks antecedent basis. Claim 9 mentions a list of optimized nucleotide sequences, but there is no mention of a most recently updated list in either claim 9 or claims 10, 14, 19, 22 or 25. Provide antecedent basis or clarify to what the recitation refers.
Claim 11, line 6, recites “the nucleotide sequence if the first portion”. It is unclear which first portion of which nucleotide sequence is referenced because claim 11, lines 1-4, determines a first portion for each nucleotide sequence in the list of optimized nucleotide sequences. A potential amendment is “removing the nucleotide sequences if [[the]] their first portions [[does]] do not meet the criterion”.
Line 2 of claims 14, 19, 22 and 25 recites “the nucleotide sequence”. It is unclear which sequence is referenced because claim 9 recites “optimized nucleotide sequences” and claim 1, step v, recites “an optimized nucleotide sequence”. Clarify which sequence(s) is referenced.
Claim 14 (line 3), claim 19 (lines 3-4), claim 22 (lines 3-4), and claim 25 (line 3) recites “such that determining and updating comprise”, which lack antecedent basis. This recitation appears to refer to a prior limitation of “determining” and “updating”, which first appears in claim 10, but none of claims 14, 19, 22 or 25 depend on claim 10. Provide antecedent basis or clarify the dependency of the claims.
Claim 17, line 4, recites “X1, X2 and X3 are independently selected from A, C, U or G” while claim 15 recites “X1, X2 and X3 are independently selected from A, C, T or G.” Thus, it’s unclear in claim 17 whether X1, X2, and X3 are selected only from A, C, U or G or selected from A, C, U, G, or T.
Claim 19, line 2, recites “a second criterion”, which renders the claim indefinite. It’s unclear if this recitation also requires “a first criterion”, or if it’s just a naming scheme and “a first criterion” is not required. The same issue is recited in claims 22 and 25 which recite “a third criterion” and “a fourth criterion”, respectively. For examination, these recitations are a naming scheme and do not require preceding criteria (i.e., the BRI of “a second criterion” is just one criterion rather than a first and a second criteria).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Claim 25 (lines 2, 5 and 8) recites a broad recitation of “at least 2” while claim 25 (lines 2-3, 5 and 8) recites a narrower limitation of “for example 3” of the broader recitation. The claim is indefinite because there is a question as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Claim 36, lines 2-3, recites a broad recitation of “generate at least one optimized nucleotide sequence” while line 4 recites a narrower limitation of “the generated optimized nucleotide sequences”. The narrower limitation requires more than “at least one”. The claim is indefinite because there is a question as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 77, lines 1-2, recites “the synthesized optimized nucleotide sequence”. It is unclear which sequence is referenced because claim 36, lines 4, synthesizes at least one optimized nucleotide sequence. Clarify which synthesized sequence is referenced.
Claim 78, step i, recites “one of the following nucleotide sequences: 5'-X1AUCUX2UX3-3', wherein X1, X2 and X3 are independently selected from A, C, U or G; and 5'- X1AUCUX2UX3-3', wherein X1, X2 and X3 are independently selected from A, C, U or G”. It’s unclear if this is a typo because both sequences are the same. Clarify whether this is a typo or if the duplication of the termination signal sequence confers a particular limitation not readily apparent.
Claim 79 recites “The in vitro synthesized nucleic acid of claim 77” which lacks antecedent basis. Claim 77 recites “the synthesized optimized nucleotide sequence” but does not recite an in vitro synthesized nucleic acid. Provide antecedent basis or clarify what the recitation refers to. For examination, claim 79 depends upon claim 78, which is where “an in vitro synthesized nucleic acid” first appears.
Claim 33 recites limitations that invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, as discussed in Claim Interpretation. The written description fails to disclose the corresponding structure, material, or acts for performing all the claimed functions and fails to clearly link the structure, material, or acts to the function. The specification merely reiterates the claimed function of step iii in claim 1 performed by the data processing system of claim 33 and does not recite a sequence of steps that constitute an algorithm. Therefore, claim 33 is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For examination, any combination of hardware and algorithms that perform the claimed functions of the data processing system will read on such limitations.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
35 USC 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 17 and 77 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 17 fails to include all the limitations of claims 15-16. Claim 15 requires the one or more termination signals have a particular sequence whereas claim 17 requires the one or more termination signals be a different sequence than claim 16.
Claim 77 fails to include all the limitations of claim 36. Claim 77 recites “the synthesized optimized nucleotide sequence generated according to the method of claim 36”, which recites a product by process. The product of “the synthesized nucleotide sequence” was previously generated by the process of claim 36. MPEP 608.01 (n).III recites “if claim 1 recites a method of making a specified product, a claim to the product set forth in claim 1 would not be a proper dependent claim if the product can be made by a method other than that recited in the base method claim, and thus, does not include the limitations of the base claim.” In the instant case, the claimed product in claim 77 can be made by another method other than the method in claim 36. See the rejection of claim 77 under 35 USC 102 for an example.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
Non-Statutory Subject Matter
Claims 32 and 34-35 are rejected under 35 U.S.C. 101 because they are directed to non-statutory subject matter (Step 1: NO). Claim 32 recites a computer program comprising instructions without reciting any structural component and therefore equates to “software per se”, which is not a statutory category of invention (MPEP 2106.03.I). Claim 34 recites a computer-readable data carrier storing a computer program without reciting that the data carrier is non-transitory, which equates to “signals per se” and is not a statutory category of invention (MPEP 2106.03.I). Claim 36 recites a data carrier signal carrying a computer program, which equates to “signals per se” and is not a statutory category of invention (MPEP 2106.03.I).
Even if claims 32 and 34-35 were amended to recite statutory subject matter, they would still be rejected under 35 U.S.C. 101 for recitation of a judicial exception without significantly more. In the interest of compact prosecution, claim 32 and 34-35 are analyzed below under 35 U.S.C. 101 as if they recited statutory subject matter.
Statutory Subject Matter
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 1-2, 4-5, 9-11, 14-17, 19, 22, 25, 32-36 and 78-80 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a product of nature without significantly more.
Step 1:
Step 1 asks whether the claims recite statutory subject matter. In the instant case, claims 1-2, 4-5, 9-11, 14-17, 19, 22 and 25 recite a method, claim 33 recites a product, claim 33 recites a system, claim 34 recites a CRM, claim 35 recites a data carrier signal which is interpreted as a non-transitory CRM, claim 36 recites a method, and claims 78-80 recite a product. As such, these claims recite statutory subject matter (Step 1: YES).
Step 2A, Prong 1:
Claims that recite statutory subject matter are analyzed under Step 2A, Prong 1 to determine if they recite any concepts that equate to an abstract idea, law of nature or natural phenomena. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claims 1 and 32-36 recite “(i) receiving an amino acid sequence, wherein the amino acid sequence encodes a peptide, polypeptide, or protein; (ii) receiving a first codon usage table, wherein the first codon usage table comprises a list of amino acids, wherein each amino acid in the table is associated with at least one codon and each codon is associated with a usage frequency; (iii) removing from the codon usage table any codons associated with a usage frequency which is less than a threshold frequency; (iv) generating a normalized codon usage table by normalising the usage frequencies of the codons not removed in step (iii); and (v) generating an optimized nucleotide sequence encoding the amino acid sequence by selecting a codon for each amino acid in the amino acid sequence based on the usage frequency of the one or more codons associated with the amino acid in the normalized codon usage table.”
Claim 2 recites “wherein normalising comprises:(a) distributing the usage frequency of each codon associated with a first amino acid and removed in step (iii) to the remaining codons associated with the first amino acid; and (b) repeating step (a) for each amino acid to produce the normalized codon usage table.”
Claim 4 recites “wherein the usage frequency of the removed codons is distributed amongst the remaining codons proportionally based on the usage frequency of each remaining codon.”
Claim 5 recites “wherein selecting a codon for each amino acid comprises:(a) identifying, in the normalized codon usage table, the one or more codons associated with a first amino acid of the amino acid sequence; (b) selecting a codon associated with the first amino acid, wherein the probability of selecting a certain codon is equal to the usage frequency associated with the codon associated with the first amino acid in the normalized codon usage table; and (c) repeating steps (a) and (b) until a codon has been selected for each amino acid in the amino acid sequence.”
Claim 9 recites “screening the list of optimized nucleotide sequences to identify and remove optimized nucleotide sequences failing to meet one or more criteria.”
Claim 10 recites “determining whether each optimized nucleotide sequence in the list, or most recently updated list, of optimized nucleotide sequences meets the criterion; and updating the list of optimized nucleotide sequences by removing any nucleotide sequence from the list, or most recently updated list, if the nucleotide sequence does not meet the criterion.”
Claim 11 recites “for each nucleotide sequence: determining whether a first portion of the nucleotide sequence meets the criterion, and wherein updating the list of optimized nucleotide sequences comprises: removing the nucleotide sequence if the first portion does not meet the criterion.”
Claim 14 recites “determining whether each optimized nucleotide sequence in the list, or most recently updated list, of optimized nucleotide sequences contains a termination signal; and updating the list of optimized nucleotide sequences by removing any nucleotide sequence from the list, or most recently updated list, if the nucleotide sequence contains one or more termination signals.”
Claim 15 recites “wherein the one or more termination signals has/have the following nucleotide sequence:5'-X1ATCTX2TX3-3', wherein X1, X2 and X3 are independently selected from A, C, T or G.”
Claim 16 recites “wherein the one or more termination signal has/have one or more of the following nucleotide sequences: TATCTGTT; and/or TTTTTT; and/or AAGCTT; and/or GAAGAGC; and/or TCTAGA.”
Claim 17 recites “wherein the one or more termination signals has/have the following nucleotide sequence: 5'-X1AUCUX2UX3-3', wherein X1, X2 and X3 are independently selected from A, C, U or G.”
Claim 19 recites “wherein a second criterion comprises the nucleotide sequence having a guanine-cytosine content within a predetermined guanine-cytosine content range, such that determining and updating comprise: determining the guanine-cytosine content of each of the optimized nucleotide sequences in the list, or most recently updated list, of optimized nucleotide sequences, wherein the guanine- cytosine content of a sequence is the percentage of bases in the nucleotide sequence that are guanine or cytosine; updating the list of optimized nucleotide sequences by removing any nucleotide sequence from the list, or most recently updated list, if its guanine-cytosine content falls outside the predetermined guanine-cytosine content range.”
Claim 22 recites “wherein a third criterion comprises the nucleotide sequence having a codon adaptation index greater than a predetermined codon adaptation index threshold, such that determining and updating comprise: determining the codon adaptation index of each of the optimized nucleotide sequences in the list, or most recently updated list, of optimized nucleotide sequences, wherein the codon adaptation index of a sequence is a measure of codon usage bias and can be a value between 0 and 1; updating the list, or most recently updated list, of optimized nucleotide sequences by removing any nucleotide sequence if its codon adaptation index is less than or equal to the predetermined codon adaptation index threshold.”
Claim 25 recites “wherein a fourth criterion comprises the nucleotide sequence not containing at least 2, for example 3, adjacent identical codons, such that determining and updating comprise: determining whether any optimized nucleotide sequence in the list, or most recently updated list, of optimized nucleotide sequences, containing at least 2, for example 3 or more, adjacent identical codons; and updating the list, or most recently updated list, of optimized nucleotide sequences by removing any nucleotide sequence if it contains at least 2, for example 3 or more, adjacent identical codons.”
Claim 36 recites “performing the computer-implemented method of claim 1 to generate at least one optimized nucleotide sequence”
Claim 78 recites “An in vitro synthesized nucleic acid comprising an optimized nucleotide sequence consisting of codons associated with a usage frequency which is greater than or equal to 10%; wherein the optimized nucleotide sequence:(i) does not contain a termination signal having one of the following nucleotide sequences: 5'-X1AUCUX2UX3-3', wherein X1, X2 and X3 are independently selected from A, C, U or G; and 5'- X1AUCUX2UX3-3', wherein X1, X2 and X3 are independently selected from A, C, U or G; (ii) does not contain any negative cis-regulatory elements and negative repeat elements; and (iii) has a codon adaptation index greater than 0.8; wherein, when divided into non-overlapping 30 nucleotide-long portions, each portion of the optimized nucleotide sequence has a guanine cytosine content range of 30% - 70%.”
Claim 79 recites “The in vitro synthesized nucleic acid of claim 77, wherein the optimized nucleotide sequence does not contain a termination signal having one of the following sequences: TATCTGTT; TTTTTT; AAGCTT; GAAGAGC; TCTAGA; UAUCUGUU; UUUUUU; AAGCUU; GAAGAGC; UCUAGA.”
Claim 80 recites “The in vitro synthesized nucleic acid of claim 78 , wherein the nucleic acid is mRNA.”
Limitations reciting a mental process.
These claims recite limitations at such a high level of generality that they equate to a mental process because they are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as concepts that can be practically performed in the human mind. The paragraphs below discuss the broadest reasonable interpretation (BRI) of the limitations in these claims that recite a mental process.
Regarding claims 1 and 32-36, steps i-ii include collecting data which is an abstract idea. Step iii includes comparing usage frequencies to a threshold, then writing down in a table only codons above the threshold. Step iv includes performing the limitations of claims 2 and 4, which includes adding a larger portion of the removed frequencies to remaining codons with the higher frequencies. Step v includes performing the limitations of claims 5, which includes repeatedly evaluating data and making determinations.
Claim 9 includes performing the limitations of claims 10-11, 14-17, 19, 22 and 25. These limitations all require evaluating previously collected data based on criteria, altering data within a table, and making selections. For example, in claims 14-17, determining if a sequence has a specific termination signal requires analyzing the sequence to identify a termination signal, and updating the list includes removing sequences from a table written on paper.
Limitations reciting a product of nature.
Claims 78-80 recite a product of nature. As described above in 35 USC 112(b), claim 79 depends on claim 78 rather than claim 77. Claim 78 recites a naturel product of a nucleic acid, which does not appear to have markedly different characteristics compared to nucleic acids that occur in nature. See MPEP 2106.04(b).II. See, e.g., Ambry Genetics, 774 F.3d at 760, 113 USPQ2d at 1244 ("Contrary to Myriad's argument, it makes no difference that the identified gene sequences are synthetically replicated. As the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible.").
As such, claims 1-2, 4-5, 9-11, 14-17, 19, 22, 25, 32-36 and 78-80 recite an abstract idea and a product of nature (Step 2A, Prong 1: YES).
Additional Elements:
Once limitations have been identified that recite a judicial exception, the claims are evaluated for additional elements. The additional elements are then analyzed under Step 2A, Prong 2 then Step 2B. The instant claims recite the following additional elements:
Claim 1 recites “A computer-implemented method for generating an optimized nucleotide sequence”
Claims 2, 4-5, 9-11, 14-17, 19, 22 and 25 recite a computer-implemented method.
Claim 32 recites “A computer program comprising instructions which, when the program is executed by a computer, cause the computer to carry out the method of claim”
Claim 33 recites “A data processing system comprising means for carrying out the method of claim 1”
Claim 34 recites “A computer-readable data carrier having stored thereon the computer program of claim 32.”
Claim 35 recites “A data carrier signal carrying the computer program of claim 32.”
Claim 36 recites “synthesizing at least one of the generated optimized nucleotide sequences.”
These above recited additional elements are analyzed below under both Step 2A, Prong 2 and Step 2B:
Step 2A, Prong 2:
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflect an improvement to a computer, technology, or technical field (MPEP § 2106.04(d)(1) and 2106.5(a)), require a particular treatment or prophylaxis for a disease or medical condition (MPEP § 2106.04(d)(2)), implement the recited judicial exception with a particular machine that is integral to the claim (MPEP § 2106.05(b)), effect a transformation or reduction of a particular article to a different state or thing (MPEP § 2106.05(c)), nor provide some other meaningful limitation (MPEP § 2106.05(e)). Rather, the claims include limitations that equate to an equivalent of the words “apply it” and/or to instructions to implement an abstract idea on a computer (MPEP § 2106.05(f)) and field of use limitations (MPEP § 2106.05(h)). The paragraphs below discuss the additional elements recited above in the instant claims.
Claims 1-2, 4-5, 9-11, 14-17, 19, 22, 25 and 32-35 recite a computer-implemented system, a computer program, a data processing system which could just be a processor, and CRM. There are no limitations requiring anything other than a generic computer and/or generic computing system. Therefore, these limitations equate to mere instructions to implement an abstract idea on a generic computer, which the courts have established does not render an abstract idea eligible in Alice Corp. 573 U.S. at 223, 110 USPQ2d at 1983.
Claim 36 recites instructions to apply the abstract idea of the generated optimized nucleotide sequences by synthesizing them (MPEP 2106.05(f)). This only recites the idea of a solution or outcome (i.e., synthesizing optimized nucleotide sequences), without reciting details for how the solution to a problem is accomplished (MPEP 2106.05(f)(1)).
Claim 36 also generally links the use of a judicial exception to a particular technological field, which cannot integrate a judicial exception into a practical application (MPEP 2106.05(h)). Claim 36 generally links the abstract idea of optimized nucleotide sequences to the technical field of sequence synthesis.
As such, claims 1-2, 4-5, 9-11, 14-17, 19, 22, 25, 32-36 and 78-80 are directed to an abstract idea and a product of nature (Step 2A, Prong 2: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). These claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims recite additional elements that equate to instructions to apply the recited exception in a generic way and/or in a generic computing environment (MPEP § 2106.05(f)) and to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The paragraphs below discuss the additional elements recited above in the instant claims.
Claims 1-2, 4-5, 9-11, 14-17, 19, 22, 25 and 32-35 recite a computer-implemented system, a computer program, a data processing system which could just be a processor, and CRM. There are no limitations requiring anything other than a generic computer and/or generic computing system. Therefore, these limitations equate to instructions to implement an abstract idea on a generic computing environment, which the courts have established does not provide an inventive concept in Intellectual Ventures I LLC v. Capital One Bank (USA), 792 F.3d 1363, 1367, 115 USPQ2d 1636, 1639 (Fed. Cir. 2015).
Claims 32 and 34-35 are interpreted as storing programs in memory, which the courts have established as a WURC function of a generic computer in Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015).
As discussed above in Step 2A, Prong 2, claim 36 equates to mere instructions to apply the abstract idea and to generally linking the use of the abstract idea to a technological environment, both of which cannot provide significantly more under Step 2B (MPEP 2106.05(f) and (h)).
When the additional elements of claims 1 and 32-36 are viewed in combination, they are WURC limitations as taught by Hughes et al. (“Hughes”; Cold Spring Harbor perspectives in biology 9, no. 1 (2017): a023812) who reviews synthetic DNA synthesis and assembly (abstract). FIG 1 shows that DNA constructs are designed using computer-aided design software then are synthesized. This demonstrates that computers and DNA synthesis are WURC in combination.
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they equate to mere instructions to apply the judicial exception, generally link the use a judicial exception to a field of use, and are WURC limitations in view of Hughes. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 1-2, 4-5, 9-11, 14-17, 19, 22, 25, 32-36 and 78-80 are not patent eligible.
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 1-2, 5, 9-11 and 32-36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gustafsson et al. (“Gustafsson”; Trends in biotechnology 22, no. 7 (2004): 346-353). Italicized text in parentheses below are the limitations of the instant claims mapped to prior art.
Claims 1 and 32-36:
Gustafsson discloses synthetic gene sequence design and optimization (abstract). Box 1 on pg. 351 shows in silico gene design indicating computer-implementation, which requires processors and memory (computer-implemented; a computer program comprising instructions; a data processing system; a computer-readable data carrier; a data carrier signal). Referring to Box 1, the gene design flow-chart begins with a target protein that has 100 amino acids, which has 1047 codon possibilities (step i) (pg. 350, col. 1, last para.). Box 1 recites acquiring an initial codon usage table comprising usage frequencies of each codon of amino acids in the target protein sequence (step ii). Referring to codon usage tables derived from a particular species, Box 1 recites “[t]hese tables can be adapted for gene design in two steps. First, a threshold level is set; that is, all frequencies below a certain value (typically between 5% and 10%) are set to zero, so that rare codons are completely eliminated. Second, the remaining frequencies are normalized so that the summed frequencies for codons for each amino acid equal 100%” (steps iii-iv). Box 1 recites “[o]nce the codon usage table has been constructed, candidate sequences are enumerated in silico by selecting codons at random with probabilities obtained from the codon usage table” and are synthesized (step v; claim 36).
Claim 2:
Box 1 recites “[f]irst, a threshold level is set; that is, all frequencies below a certain value (typically between 5% and 10%) are set to zero, so that rare codons are completely eliminated. Second, the remaining frequencies are normalized so that the summed frequencies for codons for each amino acid equal 100%.” This requires that frequencies associated with removed rare codons for each amino acid are distributed to the remaining codons for each amino acid to reach 100%.
Claim 5:
Box 1 recites “[o]nce the codon usage table has been constructed, candidate sequences are enumerated in silico by selecting codons at random with probabilities obtained from the codon usage table.” This means that the probability of randomly selecting a codon is equal to the frequency of the codon in the normalized usage table (steps a-b). This is performed for each amino acid of the target protein sequence to derive the entire sequence (step c).
Claims 9-11:
FIG 1 in Box 1 teaches that after the codon usage table is normalized each designed sequence undergoes additional filtering criterion (screening and determining). After each criterion, there are less nucleotide sequences, for example, eliminating repeats creates 1015 possibilities then eliminating unfavorable mRNA structures creates 1012 possibilities (updating by removing).
Claim 77 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Karve et al. (“Karve”; FOR ref. 1 filed 9/15/2023; WO 2018/089846 A1). Italicized text in parentheses below are the limitations of the instant claims mapped to prior art.
Karve discloses subcutaneous administration of mRNA to treat a subject with OTC deficiency (abstract) (claim 1) [155]. The mRNA is synthesized [102]. Because the mRNA is used to treat a particular protein deficiency, it is “optimized”.
The limitation “generated according to the method of claim 36” recites a product by process. MPEP 2113.I recites "[e]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In the instant case, claim 36 is the method previously performed to generate the product of “the synthesized optimized nucleotide sequence” in claim 77. Thus, the synthesized mRNA of Karve reads on the claimed product of “the synthesized optimized nucleotide sequence”, despite it not being produced by the same method as instant claim 36.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 4 is rejected under 35 USC 103 for being unpatentable over Gustafsson et al. (“Gustafsson”; Trends in biotechnology 22, no. 7 (2004): 346-353), as applied to claims 1-2, in view of Govindarajan et al. (“Govindarajan”; US 8,825,411 B2).
The limitations of claims 1-2 are taught above by Gustafsson under 35 USC 102. Italicized text in parentheses below are the limitations of the instant claims mapped to prior art.
Claim 4:
Gustafsson recites in Box 1 on pg. 351 “[f]irst, a threshold level is set; that is, all frequencies below a certain value (typically between 5% and 10%) are set to zero, so that rare codons are completely eliminated. Second, the remaining frequencies are normalized so that the summed frequencies for codons for each amino acid equal 100%.” However, Gustafsson does not describe how the normalization is performed.
Govindarajan designs and synthesizes synthetic nucleic acids (abstract) and describes concerns regarding biases of codon usage in codon usage tables (FIG 24). To address such a concern, codons with a frequency less than 0.05 are removed from the table. This generates codon frequencies for each amino acid that do not sum to 1. For amino acids that do not sum to 1, the remaining frequencies are normalized by dividing the frequency of each remaining codon by the sum of the remaining codon frequencies for each amino acid (col. 7, lines 29-50). This results in the removed frequencies being distributed proportionally to the remaining frequencies because each remaining frequency is renormalized to sum to 1.
It would have been prima facie obvious to have modified the normalizing procedure of Gustafsson that makes remaining codon frequencies sum to 1 by dividing the frequency of each remaining codon for each amino acid by the sum of the remaining frequencies of the codons of each amino acid as taught by Govindarajan. Motivation is that Govindarajan provides the normalizing procedure that Gustafsson alludes to but fails to describe in detail, and one of skill in the art would want to renormalize the frequencies to sum to 1. There would have been a reasonable expectation of success because the modification requires implementing the normalization strategy of Govindarajan that results in the same outcome of frequencies summed to 1 as taught by Gustafsson.
Claims 14-16 are rejected under 35 USC 103 for being unpatentable over Gustafsson et al. (“Gustafsson”; Trends in biotechnology 22, no. 7 (2004): 346-353), as applied to claims 1 and 9, in view of Sohn et al. (“Sohn”; Proceedings of the National Academy of Sciences 102, no. 1 (2005): 75-80).
The limitations of claims 1 and 9 are taught above by Gustafsson under 35 USC 102. Italicized text in parentheses below are the limitations of the instant claims mapped to prior art.
Claims 14-16:
Gustafsson describes in Box 1 on pg. 351 having a target protein sequence then selecting from a normalized table of codon frequencies different potential nucleotide sequences of the target protein. Each potential sequence undergoes a series of criterion filtering that reduces the number of potential sequences (determining; updating by removing). However, Gustafsson does not teach filtering based on whether a potential sequence contains a particular termination signal.
Sohn describes sequence-specific termination by T7 RNA polymerase (title). Sohn teaches that E. coli rrnB terminator t1 contains a sequence-specific termination signal consisting of an 8-bp conserved sequence, TATCTGTT (abstract).
It would have been prima facie obvious to have modified the nucleotide sequence optimization design process of Gustafsson that filters potential nucleotide sequences based on design criteria by incorporating a design criterion that determines whether a premature termination signal is present, such as the one described by Sohn, then removing potential sequences with the premature termination signal. Motivation is that if a premature termination signal is found in the middle of the optimized nucleotide sequence, then the resultant protein will be truncated, which is undesirable. There would have been a reasonable expectation of success because identifying a termination signal requires scanning sequences for known termination signals.
Claim 17 is rejected under 35 USC 103 for being unpatentable over Gustafsson et al. (“Gustafsson”; Trends in biotechnology 22, no. 7 (2004): 346-353) in view of Sohn et al. (“Sohn”; Proceedings of the National Academy of Sciences 102, no. 1 (2005): 75-80), as applied to claims 1, 9 and 14-16, and in further view of Hobdey et al. (“Hobdey”; Journal of virology 84, no. 16 (2010): 8072-8084).
The limitations of claims 1 and 9 are taught above by Gustafsson under 35 USC 102. The limitations of claims 14-16 are taught above by Gustafsson in view of Sohn. Italicized text in parentheses below are the limitations of the instant claims mapped to prior art.
Claim 17:
Gustafsson describes in Box 1 on pg. 351 having a target protein sequence then selecting from a normalized table of codon frequencies different potential nucleotide sequences of the target protein sequence. Each potential sequence undergoes a series of criterion filtering that reduces the number of potential sequences (determining; updating by removing). However, Gustafsson and Sohn do not filter based for a particular sequence listed in instant claim 17.
Hobdey evaluates the role of residue 5 in poliovirus polymerase (title). When generating poliovirus RNA templates using T7 transcription from linearized pRNA2, a 760-nt fragment was produced including the internal ribosome entry site of the poliovirus. This was because a T7 polymerase abortive sequence of 5′-UAUCUGUU-3′ was found after the IRES element in the pRNA2 cDNA (pg. 8077, col. 2, para. 4).
It would have been prima facie obvious to have modified the nucleotide sequence optimization design process of Gustafsson that filters potential nucleotide sequences based on design criteria by incorporating a design criterion that determines whether a premature termination signal is present, such as the one described by Hobdey, then removing potential sequences with the premature termination signal. Motivation is that if a premature termination signal is found in the middle of the optimized nucleotide sequence, then the resultant protein will be truncated, which is undesirable. There would have been a reasonable expectation of success because identifying a termination signal requires scanning sequences for known termination signals.
Claims 19, 22, and 25 are rejected under 35 USC 103 for being unpatentable over Gustafsson et al. (“Gustafsson”; Trends in biotechnology 22, no. 7 (2004): 346-353), as applied to claims 1 and 9, in view of Liu et al. (“Liu”; US patent ref. 1 on IDS filed 9/15/2023; US 2011//0081708 A1).
The limitations of claims 1 and 9 are taught above by Gustafsson under 35 USC 102. Italicized text in parentheses below are the limitations of the instant claims mapped to prior art.
Claims 19, 22 and 25:
Gustafsson describes, in Box 1 on pg. 351, a target protein sequence then selects from a normalized table of codon frequencies different potential nucleotide sequences of the target protein. Each potential sequence undergoes a series of criterion filtering that reduces the number of potential sequences (determining; updating by removing). Two criteria are eliminating extreme GC content and direct repeats (Box 1, steps ii-iii). Gustafsson also mentions codon adaptation index (pg. 347, col. 1, para. 1). However, Gustafsson does not filter sequences based on a GC content threshold or adaptation index threshold nor filters out sequences that contain at least 2 adjacent identical codons.
Liu discloses method of sequence optimization for recombinant protein expression (abstract). Liu describes different optimization criteria: “[s]ome bases of long or short tandem simple sequence repeat (SSR) are preferably mutated using codon degeneracy” [37] (at least 2 adjacent identical codons); “the optimal range for CAI is preferably from 0.8 to 1.0” [40] (predetermined codon adaptation index threshold); and “GC-content of mRNA is also preferably monitored. An ideal range for GC % is approximately 30-70%” [46] (predetermined guanine-cytosine content range).
It would have been prima facie obvious to have modified the gene design method of Gustafsson that filters potential nucleotide sequences through sequential criteria, wherein each criterion reduces the number of potential sequences, by also filtering for repeated adjacent identical codons, GC content, and CAI as taught by Liu. Motivation is taught by Liu who recites that filtering for SSRs, GC, and CAI content has advantages of reducing polymerase slippage [37], reducing problems with PCR amplification and gene cloning [46], and boosting protein translation efficiency [40], respectively. There would have been a reasonable expectation of success because the gene design method of Gustafsson allows for additional design criteria to optimize sequences (Box 1 on pg. 351).
Claims 78-80 are rejected under 35 USC 103 for being unpatentable over Liu et al. (“Liu”; US patent ref. 1 on IDS filed 9/15/2023; US 2011//0081708 A1) in view of Gustafsson et al. (“Gustafsson”; Trends in biotechnology 22, no. 7 (2004): 346-353) and Hobdey et al. (“Hobdey”; Journal of virology 84, no. 16 (2010): 8072-8084).
Italicized text in parentheses below are the limitations of the instant claims mapped to prior art. As discussed above in 35 USC 112(b), claim 79 depends upon claim 78 rather than claim 77.
Claims 78-80:
Regarding the preamble of claim 78 and claim 80, Liu designs and synthesizes an optimized gene sequence of a protein [65] and the sequence may be mRNA [46] (wherein the nucleic acid is mRNA). Codon usage is a parameter that is optimized (abstract) (an in vitro synthesized nucleic acid comprising an optimized nucleotide sequence consisting of codons associated with a usage frequency), but the codon usage is not at least 10%.
Gustafsson discloses an optimization method to design gene sequences for proteins (abstract). Gustafsson recites “a threshold level is set; that is, all frequencies below a certain value (typically between 5% and 10%) are set to zero, so that rare codons are completely eliminated” (Box 1 on pg. 351). It would have been prima facie obvious to modify Liu’s method of optimizing codon usage by eliminating codons that have a frequency usage below 10% because Gustafsson teaches in Box 1 that this removes rare codons. There would have been a reasonable expectation of success because Gustafsson teaches in Box 1 that codon usage frequencies are readily available in databases, which could be acquired for Liu to then optimize the frequencies.
Regarding step (i) and claim 79, Liu optimizes for parameters that affect protein expression in optimized gene sequences to boost protein expression (abstract), but does not teach that gene sequences lack the specific termination signals of instant claim 78, step i.
Hobdey evaluates the role of residue 5 in poliovirus polymerase (title). When generating poliovirus RNA templates using T7 transcription from linearized pRNA2, a 760-nt fragment was produced including the internal ribosome entry site of the poliovirus. This was because a T7 polymerase abortive sequence of 5′-UAUCUGUU-3′ was found after the IRES element in the pRNA2 cDNA (pg. 8077, col. 2, para. 4). It would have been prima facie obvious to have modified the optimized gene sequence design of Liu by eliminating any sequences that contain the termination signal 5′-UAUCUGUU-3′ taught by Hobdey. Motivation is that a premature termination signal in the middle of the optimized gene sequence would result in a truncated protein, which is undesirable. This aligns with Liu’s motivation to optimize sequences based on parameters that affect protein expression (abstract). There would have been a reasonable expectation of success because identifying a termination signal merely scanning the sequences for known termination signals.
Regarding step (ii), although Liu does not teach that the optimized gene sequence does not contain negative cis-regulatory elements or negative repeats, instant step (ii) is prima facie obvious over the teachings of Liu. Liu discloses “[s]ome bases of long or short tandem simple sequence repeat (SSR) are preferably mutated using codon degeneracy to break the repeats to reduce polymerase slippage, to thus reduce premature protein or protein mutations” [37]. Liu teaches that cis-regulatory sequences should be considered [4] and optimizes for direct, reverse, and dyad repeats [52-53]. Because Liu is directed to optimizing a gene sequence based on factors affecting protein expression (abstract of Liu), it would have been prima facie obvious to one of skill to remove negative cis-regulatory elements and repeat elements that reduce protein expression. There would have been a reasonable expectation of success because Liu allows optimization based on any parameter that optimizes gene expression [48].
Regarding step (iii), Liu discloses “the optimal range for CAI is preferably from 0.8 to 1.0” [40].
Regarding the wherein clause of claim 78, Liu discloses “GC-content of mRNA is also preferably monitored. An ideal range for GC % is approximately 30-70% … One is the global GC % which is averaged along the whole sequence; the other is more useful, which is the local GC % calculated within a shifted ‘window’ of fixed size (e.g. 60 bp)” [46]. Although Liu discloses a window of 60bp, a window of 30bp would have been prima facie obvious over the teachings of Liu. MPEP 2144.05.II discusses routine optimization and recites that a result-effective variable may provide motivation to experiment to reach another workable product or process. In the instant case, the result-effective variable is window length for local GC% because Liu teaches that it can reduce strong stem-loop secondary structures [46]. Thus, it would have been prima facie obvious to have optimized the window size of Liu to reach 30bp windows with a local GC% between 30-70%.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 77-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-3, 85 and 124 of copending Application No. 18/552,165 (hereinafter “App ‘165”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of App ‘165 anticipate the instant claims. Claims 2-3 of App ‘165 read on instant claims 78-80. Claims 85 and 124 of App ‘165 read on instant claim 77.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 77-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 78 and 90 of copending Application No. 17/923,497 (hereinafter “App ‘497”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of App ‘497 anticipate the instant claims. Claims 2-3 of App ’497 read on instant claims 78-80. Claims 78 and 90 of App ‘497 read on instant claim 77.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 14-16 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-7, and 9 of copending Application No. 18/580,463 (hereinafter “App ‘463”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of App ‘463 anticipate the instant claims. Claims 6-7 of App ‘463 read on instant claims 1 and 22. Claim 9 of App ‘463 reads on instant claims 14-16.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Claim 77 is patent-eligible under 35 USC 101 because it does not recite a judicial exception.
Notable, but not relied upon, prior art includes: Usdin (Genome research 18, no. 7 (2008): 1011-1019) effects of coding and non-coding effect of simple tandem repeats on expression (abstract) (Table 1). Oberortner et al. (ACS synthetic biology 6, no. 3 (2017): 485-496) sequence optimization pipeline (abstract). Tran et al. (Wo 2021/168052 A1; effective filing date 02/18/2020; has different authors) in Table 2 recites termination signals [263].
Inquiries
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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