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 .
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 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.
Claim Status
Claims 26-28, 32-46, 50, and 207 are pending.
Claims 1-25, 29-31, 47-49, and 51-206 are canceled.
Claims 26-28, 32-46, 50, and 207 are rejected.
Priority
The instant Application claims domestic benefit to US provisional applications 63/159,880 and 63/159,879, filed Mar 11 2021.
Applicant's claim for the benefit of a prior-filed application, PCT/US2022/020049, filed Mar 11 2022, is acknowledged.
Accordingly, each of claims 26-28, 32-46, 50, and 207 are afforded the effective filing date of Mar 11 2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on Sep 8 2023 and Mar 19 2026 are in compliance with the provisions of 37 CFR 1.97 and have therefore been considered. Signed copies of the IDS documents are included with this Office Action.
Drawings
The Drawings submitted Sep 8 2023 are accepted.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because FIG. 4 includes 7 different peptide sequences which require a SEQ ID NO, and [0093] specifically references SEQ ID NO:1-4.
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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.
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that FIG. 4 and [0093; 0122; 0134] contains such sequences. Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - 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.
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 amendments submitted Mar 27 2024 are accepted herein.
The disclosure is objected to for the following informalities. It is noted that for purposes of the instant Office Action, any reference to the specification pertains to the specification as originally filed on Sep 8 2023.
Hyperlinks
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Non-limiting examples include paragraph [0132]. Applicant will note that this is exemplary and other instances may exist. It is requested that all instances be corrected.
Appropriate correction for all objections to the specification is required.
Claim Interpretation
Claim Terminology
Claim 27 recites “wherein the one or more databases comprises an expanded human proteome database… wherein the plurality of searches comprises a linear human proteome search for the peptide sequence within the expanded human proteome database”. Under the BRI, claim 27 limits one or more of the one or more databases to an expanded human proteome database but limits all searches of the plurality of searches performed in claim 26 to a linear human proteome search for the peptide sequence within the expanded human proteome database. While claim 26 requires only the performance of only one search in one database, the claims also encompass more than one search in more than one database. In the embodiment where multiple searches are performed in multiple databases, the databases are limited only to comprise one or more expanded human proteome databases, indicating that other databases are within the scope of the claim, but the scope of claim 27 is limited to all searches being required to be performed in the expanded human proteome database(s). If Applicant did not intend to limit the claim as described, it is suggested to amend the limitation to “wherein one or more of the plurality of searches comprises…” to indicate that other types of searches in other databases are encompassed within the embodiment. Claim 37 is similarly interpreted.
Claim Rejections - 35 USC § 112
35 U.S.C. 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.
Claims 33-36, 39-45, and 207 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 33 recites “wherein the plurality of searches comprises a linear human genome search of translations of the human genome database”. However, claim 27, from which claim 33 depends, already requires “wherein the plurality of searches comprises a linear human proteome search for the peptide sequence within the expanded human proteome database”, which, as described in the above claim interpretation section, already limits the plurality of searches recited in claim 26. Therefore it is not clear whether claim 33 intends to require that additional types of searches are performed in additional types of databases, or if it intends to replace the searches required in claim 26, which would result in issues regarding 35 USC 112(d). For compact examination, it is assumed that the limitations in claims 27 and 33 should be amended to recite “wherein one or more of plurality of searches…” to indicate that a plurality of types of searches are encompassed within the scope of the claims. Claims 35 and 39-44 are similarly rejected. Further regarding claim 33, even if the claim is interpreted to encompass a plurality of types of searches in the interest of compact examination, it is noted that claim 26 requires only one search to be performed, and as claim 27 already limits that search to a linear human proteome search for the peptide sequence within the expanded human proteome database and claim 33 does not require more than one search to be performed, under the broadest reasonable interpretation, the searches described in claim 33 are not required to be performed within the metes and bounds of the claim. Claims 34-36, 39-46, and 207 are similarly interpreted.
Claim 207 recites “wherein the plurality of searches are ordered…”. It is unclear whether the wherein clause is intended to require performing the ordering within the metes and bounds of the claimed invention, or if it is only further limiting the plurality of searches such that performing the ordering is not required within the metes and bounds of the invention. As set forth in MPEP 2111.04.I, “wherein” clauses raise the question as to the limiting effect of the language in a claim. As the claims do not recite an active performance of the ordering, the metes and bounds of the claims are unclear. For compact examination, it is assumed that the ordering is not required to be performed. The rejection may be overcome by clarifying what steps are required to be performed. Claims 41-45 are rejected based on their dependency from claim 207.
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 26-28, 32-46, 50, and 207 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to a non-transitory computer-readable medium, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) as well as a law of nature or a natural phenomenon are as follows:
Independent claim 26: perform one or more searches of a plurality of searches of the peptide sequence within one or more databases, wherein each respective search of the plurality of searches has a random hit rate that is based at least in part on a number of random sequences found by the respective search; and
determine a putative source associated with the peptide sequence, wherein the putative source is identified by the respective search of the plurality of searches having the lowest random hit rate for which a match for the searched peptide sequence is found.
Dependent claim 32: identify whether the peptide sequence is putatively translated from messenger RNA or non-coding RNA.
Dependent claim 41: wherein the putative source is determined to be unidentified when the trans-spliced search does not find computer-readable representations of peptide fragments that can be trans- spliced to match the peptide sequence.
Dependent claim 45: halt advancement of the workflow to a subsequent search of the plurality of searches when the putative source is determined for the peptide sequence.
Dependent claim 46: wherein the peptide sequence comprises at least one ambiguous residue;
generate a plurality of permutated peptide sequences each comprising a potential residue for each of the at least one ambiguous residue such that the plurality of permutated peptide sequences comprises leucine and isoleucine as potential residues; and
determine the putative source of the peptide sequence such that the putative source is identified by a search of the plurality of searches having the lowest random hit rate for which a match of any of the plurality of permutated peptide sequences is found.
Dependent claim 207: wherein the plurality of searches are ordered in order of increasing random hit rate such that… the one or more searches of the plurality of searches (are performed) in order of increasing random hit rate.
Dependent claims 27-28, 33-40, and 42-44 recite further steps that limit the judicial exceptions in independent claim 26 and, as such, also are directed to those abstract ideas. For example, claims 27-28 further limit the one or more databases being searched to an expanded human proteome database which comprises computer-readable representations of translations from messenger ribonucleic acids (RNAs), non-coding RNAs, and micro RNAs, long non-coding RNAs, and human endogenous retroviruses, and further limits the searches to a linear human proteome search for the peptide sequence within the expanded human proteome database; claims 33-34 further limit the one or more databases being searched to a human genome database, and further limit the searches to a linear human genome search, which excludes portions of the human genome from which the messenger RNA and the non-coding RNA of the expanded human proteome database are transcribed, of translations of the human genome database; claims 35-36 further limit the plurality of searches to a linear mismatch search for peptides having a single mismatch to the peptide sequence within the expanded human proteome database; claims 37-38 further limit the one or more databases being searched to a non-endogenous proteome database comprising computer-readable representations of proteins translated from RNA from non-endogenous organisms and/or proteins synthesized by non-endogenous organisms which were mapped using BLAST, and the plurality of searches to a linear non-endogenous search for the peptide sequence within the non-endogenous proteome database; claim 39 further limits the plurality of searches to a cis-spliced search, within the expanded human proteome database, for peptide fragments that can be cis-spliced to match the peptide sequence; claim 40 further limits the plurality of searches to a trans-spliced search, within the expanded human proteome database, for computer-readable representations of peptide fragments that can be trans-spliced to match the peptide sequence; and claims 42-44 further limits the one or more databases being searched to a human genome database and a non-endogenous proteome database, and further limit the order and type of searches.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually determine a source for a peptide sequence based on one or more searches. Without further detail as to the methodology involved in “performing one or more searches” and “determining a putative source” of a peptide sequence, under the BRI, one may simply, for example, visually, or using pen an paper, search one or more databases, which are unlimited in size, for a hit for a peptide sequence, which is unlimited in size, to determine a source of the peptide based on a lowest random hit rate, which is interpreted as choosing the database with the lowest random hit rate. One may mentally determine the order of the searches to be performed based on the random hit rate. One may further generate a plurality of permuted peptide sequences with a leucine and isoleucine as potential residues replacing ambiguous residues and perform the searches with the permuted peptide sequences to determine a source. The acts of performing the search and making the determination therefore encompass observations, evaluations, and judgments, which are concepts able to be performed in the human mind. Further, the act of ordering the searches based on the random hit rates requires mathematical techniques as the only supported embodiments, as the limitation describes a mathematical concept in words.
Therefore, claim 26 and those claims dependent therefrom recite an abstract idea [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Independent claim 26: receive, as an input, a peptide sequence; and
provide, as an output, the putative source.
Dependent claim 50 further limits the recited additional elements in the claims by limiting the peptide sequence to a de novo peptide sequence determined via mass spectrometry.
The claims also include non-abstract computing elements. For example, independent claim 26 includes a non-transitory computer-readable medium configured to communicate with one or more processor(s) of a computational device, the non-transitory computer-readable medium including instructions thereon, that when executed by the processor(s), cause the computational device to perform the actions in the claim.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to data gathering, such as “receiving” a peptide sequence as input, where the sequence was determined via mass spectrometry as a de novo peptide sequence as in claim 50,, and to data outputting, such as “providing” a putative source as output, perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
Further steps directed to additional non-abstract computer elements do not describe any specific computational steps by which the “computer parts” perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer, such as the computer-readable recording media, are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, and therefore the claim does not integrate that judicial exceptions into a practical application. The courts have weighed in and consistently maintained that when, for example, a memory, display, processor, machine, etc.… are recited so generically (i.e., no details are provided) that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (MPEP 2106.05(f)).
The specification as published discloses that the invention addresses shortcomings in querying data sources at [0003], but does not provide a clear explanation for how the additional elements provide these improvements. Therefore, the additional elements do not clearly improve the functioning of a computer, or comprise an improvement to any other technical field. Further, the additional elements do not clearly affect a particular treatment; they do not clearly require or set forth a particular machine; they do not clearly effect a transformation of matter; nor do they clearly provide a nonconventional or unconventional step (MPEP2106.04(d)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the prior art to Seidler et al. (Proteomics, 2010, 10(4), pp.634-649; newly cited) discloses that de novo peptide sequencing by mass spectrometry is a data gathering element that is routine, well-understood and conventional in the art. The entire document is relevant. Further, the courts have found that receiving and outputting data are well-understood, routine, and conventional functions of a computer when claimed in a merely generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(II)(i)). As such, the claims simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (MPEP2106.05(d)). The data gathering steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
With respect to claims 26 and those claims dependent therefrom, the computer-related elements or the general purpose computer do not rise to the level of significantly more than the judicial exception. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, which the courts have found to not provide significantly more when recited in a claim with a judicial exception (Alice Corp., 573 U.S. at 225-26, 110 USPQ2d at 1984; see MPEP 2106.05(A)). The specification also notes that computer processors and systems, as example, are commercially available or widely used at [0046-0049]. The additional elements are set forth at such a high level of generality that they can be met by a general purpose computer. Therefore, the computer components constitute no more than a general link to a technological environment, which is insufficient to constitute an inventive concept that would render the claims significantly more than the judicial exceptions (see MPEP 2106.05(b)I-III).
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself [Step 2B: NO; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
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.
A. Claims 26-27, 32-39, 42-43, 45-46, 50, and 207 are rejected under 35 U.S.C. 103 as being unpatentable over the features of Erhard et al. (Cancer Immunology Research, 2020, 8(8):1018-1026; newly cited) in view of Hather et al. (Proteomics, 2010, 10(12):2369-2376; newly cited).
Claim 26 discloses a non- transitory computer-readable medium configured to communicate with one or more processor(s) of a computational device, the non-transitory computer-readable medium including instructions thereon, that when executed by the processor(s), cause the computational device perform steps.
The prior art to Erhard discloses a mass spectrometric approach to show an underappreciated class of epitopes that accounts for up to 15% of HLA-I peptides for certain HLA alleles in various tumors and patients, where the peptides are translated from cryptic open reading frames in supposedly noncoding regions in the genome and are mostly unidentifiable with conventional computational analyses of mass spectrometry (MS) data (abstract). Erhard teaches that their approach is called Peptide-PRISM which is available as software/code (p. 1020, col. 1, par. 4), which reads on a non-transitory computer-readable medium as instantly claimed.
The steps of claim 26 comprise:
receive, as an input, a peptide sequence;
Erhard teaches analyzing immunopeptidome datasets (i.e., a peptide sequence) (p. 1018, col. 2, par. 3 through p. 1019, col. 1, par. 2)
perform one or more searches of a plurality of searches of the peptide sequence within one or more databases, wherein each respective search of the plurality of searches has a random hit rate that is based at least in part on a number of random sequences found by the respective search;
Erhard teaches using an algorithm to scan (i.e., search) through a 6-frame translation of the genome, a 3-frame translation of the transcriptome, a decoy database, a PCPS peptide database (normal and reverse cis-spliced peptides with a maximal intervening distance of 25), the human proteome with all possible substitutions of a single amino acid, and any peptide that could be generated from ribosomal frameshifting in the human proteome (1020, col. 2, par. 3 through p. 1021, col. 1, par. 1), and categorizing the all identified string matches from the 6-frame translated genome and 3-frame translated transcriptome were categorized as follows: (i) Coding sequence (CDS): in-frame with annotated protein; (ii) 50-UTR: contained in annotated mRNA, consistently with its introns, overlapping with 50-UTR; (iii) Off-Frame: off-frame contained in the coding sequence, consistently with its introns; (iv) 30-UTR: all others that are introns, consistently contained in an mRNA; (v) noncoding (nc) RNA: consistently contained in an annotated ncRNA; (vi) Intronic: intersecting any annotated intron; or (vii) Intergenic (i.e., a plurality of searches of the peptide sequence within one or more databases) (p. 1019, col. 1, par. 3 through col. 2, par. 3). Both the different databases as well as the categories read on a plurality of searches of the peptide sequence within one or more databases as instantly claimed, because the categories are based on the databases. Erhard teaches calculating expected numbers of true and false targets, based on target/decoy status (i.e., random sequences), to compute FDRs per peptide length and category (i.e., each search has a random hit rate) (p. 1019, col. 2, par. 4-5). The instant specification as published discloses that the “terms “random hit rate” and “false discovery rate” are used interchangeably herein and are understood to mean a frequency at which randomly generated inputs are found by a search of a database” [0043].
determine a putative source associated with the peptide sequence, wherein the putative source is identified by the respective search of the plurality of searches having the lowest random hit rate for which a match for the searched peptide sequence is found; and
Erhard teaches that each remaining peptide was identified to originate from a location on the genome (i.e., a putative source) (p. 1019, col. 2, par. 6). Erhard teaches that Peptide-PRISM utilizes mixture modeling to deconvolute the overall de novo score distribution into components of false and true identifications to then stratify the sequence search space into 9 categories in addition to conventional peptides to identify and classify cryptic peptides (i.e., a putative source) (p. 1020, col. 2, par. 2 through p. 1021, col. 1, par. 1; Figure 1). Erhard teaches that Peptide-PRIMS allows for FDR control per stratum to identify the peptide categories (p. 1021, col. 1, par. 1). Erhard teaches in cases with multiple matching database peptides per spectra, they used a biologically motivated heuristic to select a single candidate by stratifying the database into biologically meaningful categories and prioritizing these categories to select the most parsimonious candidate (p. 1020, col. 2, par. 1; p 1019, col. 1, par. 4 through col. 2, par. 1).
Erhard does not teach selecting the category for each spectra based on the lowest FDR for the spectra, or identifying the putative source based on the lowest random hit rate as instantly claimed. However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify, in the course of routine experimentation and with a reasonable expectation of success, the method of Erhard. It would have been obvious to assign the final category to the peptide based on the category with the lowest FDR per stratum rather than the prioritized biologically meaningful categories taught by Erhard because FDR scores for randomized matches in decoy databases are known to approximate the distribution of scores for incorrect nonrandomized matches, as taught by Hather (p. 2370, col. 1, par. 3), and it is considered that one of ordinary skill in the art would have recognized the predictable result of choosing the most likely category for the spectrum. The motivation would have been to avoid identifying incorrect peptides or proteins, as taught by Hather (p. 2369, col. 2, par. 2).
provide, as an output, the putative source.
Erhard teaches displaying the percentage of peptides to their categories (Figure 1), which are presented in data tables (p. 1022, col. 2, par. 2, pointing to Supplementary Table S3). Both the graphs and data tables read on outputs of the putative source as instantly claimed.
Regarding claim 27, Erhard in view of Hather teaches claim 26. Claim 27 further adds that the one or more databases comprises an expanded human proteome database, that the expanded human proteome database comprises computer-readable representations of translations from messenger ribonucleic acids (RNAs) and non-coding RNAs, and that the plurality of searches comprises a linear human proteome search for the peptide sequence within the expanded human proteome database.
Erhard teaches searching (i.e., a linear human proteome search) a database (i.e., an expanded human proteome database) of the 3-frame translation (i.e., computer-readable representations) of the transcriptome (Ensembl 90) (p. 1019, col. 1, par. 3), which contains all coding (i.e., messenger RNAs) and noncoding splice variants (i.e., non-coding RNAs) (p. 1020, col. 2, par. 3). As Erhard teaches a 3-frame translation of the entire transcriptome, it is considered that Erhard fairly teaches a linear human proteome search as instantly claimed.
Regarding claim 32, Erhard in view of Hather teaches claims 26-27. Claim 32 further adds identifying whether the peptide sequence is putatively translated from messenger RNA or non-coding RNA.
Erhard teaches classifying peptide spectrum into categories, including as (i) coding sequence (CDS): in-frame with annotated protein (i.e., messenger RNA) or (v) noncoding (nc) RNA: consistently contained in an annotated ncRNA (p. 1019, col. 1, par. 4).
Regarding claim 33, Erhard in view of Hather teaches claims 26-27. Claim 33 further adds that the one or more databases comprises a human genome database and that the plurality of searches comprises a linear human genome search of translations of the human genome database.
Erhard teaches searching the 6-frame translation of the genome (p. 1019, col. 1, par. 3). As Erhard teaches a 6-frame translation of the entire genome, it is considered that Erhard fairly teaches a linear human proteome search as instantly claimed.
Regarding claim 34, Erhard in view of Hather teaches claims 26-27 and 33. Claim 34 further adds that the linear human genome search excludes portions of the human genome from which the messenger RNA and the non-coding RNA of the expanded human proteome database are transcribed and includes remaining portions of the human genome. Erhard teaches a biologically motivated heuristic to select a single candidate when peptides matched multiple databases by stratifying the database into biologically meaningful categories and prioritized these categories to select the most parsimonious candidate (p. 1020, col. 2, par. 1). Erhard does not teach excluding portions of the human genome from which the messenger RNA and the non-coding RNA as instantly claimed.
However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify, in the course of routine experimentation and with a reasonable expectation of success, the method of Erhard. It would have been obvious to one of ordinary skill in the art to exclude portions of the human genome from which the messenger RNA and the non-coding RNA because Erhard teaches that their strategy is equivalent to first searching the proteome, then searching the 5’-UTR with all so far unmapped sequences, etc, (p. 1020, col. 2, par. 1) through the prioritized categories (CDS > 5’-UTR > Off-Frame > Frameshift > 3’-UTR > ncRNA > Substitution > Intronic > Intergenic > PCPS) (p. 1019, col. 1, par. 4 through col. 2, par. 1), where the category “Intergenic” at least reads on the remaining parts of the genome when the messenger and non-coding RNA is excluded. Therefore, one of ordinary skill in the art would have understood that equivalent, predictable results would be achieved by making separate databases for each category and performing the searches, rather than assigning categories based on searching overlapping databases and a prioritized classification procedure, because Erhard teaches that those methods are equivalent.
Regarding claims 35-36, Erhard in view of Hather teaches claims 26-27. Claim 35 further adds that the plurality of searches comprises a linear mismatch search for peptides having a mismatch to the peptide sequence within the expanded human proteome database. Claim 36 further adds that the linear mismatch search is a search for peptide sequences having only a single mismatch to the peptide sequence.
Erhard teaches searching the 6-frame translation of the genome and the 3-frame translation of the transcriptome includes a search for all possible single amino acid substitutions (i.e., a linear mismatch search) (p. 1019, col. 1, par. 3).
Regarding claims 37-38, Erhard in view of Hather teaches claim 26. Claim 37 further adds that the one or more databases comprises a non-endogenous proteome database comprising computer-readable representations of proteins translated from RNA from non-endogenous organisms and/or proteins synthesized by non-endogenous organisms, and that the plurality of searches comprises a linear non-endogenous search for the peptide sequence within the non-endogenous proteome database. Claim 38 further adds that the non-endogenous proteome database comprises sequences of non-endogenous organisms mapped using a Basic Local Alignment Search Tool (BLAST). Erhard does not teach these claims.
However, Hather teaches analyzing data sets of N2 Caenorhabditis elegans mitochondria and a protein standard mixture of 54 proteins (BIATECH-54 mix), consisting of 38 Shewanella oneidensis proteins plus 16 proteins from other species (p. 2370, col. 2, par. 2). Hather teaches searching the datasets against a database of known contaminants and a decoy database of Rhodobacter sphaeroides appended to increase its complexity (i.e., a linear non-endogenous search within a database of proteins synthesized by non-endogenous organisms) (p. 2370, col. 2, par. 4). As Hather teaches databases with sequences assigned to certain species, it is considered that Hather fairly teaches a “non-endogenous proteome database comprises sequences of non-endogenous organisms mapped using a Basic Local Alignment Search Tool (BLAST)”, which is interpreted as a product-by-process limitation (see MPEP 2113). The claim does not require the mapping the sequences using BLAST, which would merely result in the assignment of the sequences to the database, but only requires using a database which is structurally equivalent to the a database comprising sequences mapped using BLAST.
Regarding claims 37-38, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, Erhard and Hather because each reference discloses methods for determining false discovery rates using randomized or decoy databases. The motivation to include proteins of non-endogenous organisms would have been to increase the complexity of the database, as taught by Hather (p. 2370, col. 2, par. 4).
Regarding claim 39, Erhard in view of Hather teaches claims 26-27. Claim 39 further adds that the plurality of searches comprises a cis-spliced search, within the expanded human proteome database, for peptide fragments that can be cis-spliced to match the peptide sequence.
Erhard teaches searching for cis-spliced protein sequences (p. 1019, col. 1, par. 3).
Regarding claim 207, Erhard in view of Hather teaches claims 26-27. Claim 207 further adds that the plurality of searches are ordered in order of increasing random hit rate and then performing the searches of the plurality of searches in order of increasing random hit rate.
Erhard teaches that each remaining peptide was identified to originate from a location on the genome (i.e., a putative source) (p. 1019, col. 2, par. 6). Erhard teaches that Peptide-PRISM utilizes mixture modeling to deconvolute the overall de novo score distribution into components of false and true identifications to then stratify the sequence search space into 9 categories in addition to conventional peptides to identify and classify cryptic peptides (i.e., a putative source) (p. 1020, col. 2, par. 2 through p. 1021, col. 1, par. 1; Figure 1). Erhard teaches that Peptide-PRIMS allows for FDR control per stratum to identify the peptide categories (p. 1021, col. 1, par. 1). Erhard teaches in cases with multiple matching database peptides per spectra, they used a biologically motivated heuristic to select a single candidate by stratifying the database into biologically meaningful categories and prioritizing these categories to select the most parsimonious candidate (p. 1020, col. 2, par. 1; p 1019, col. 1, par. 4 through col. 2, par. 1).
Erhard does not teach performing the searches of the plurality of searches in order of increasing random hit rate as instantly claimed. However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify, in the course of routine experimentation and with a reasonable expectation of success, the method of Erhard. It would have been obvious to perform the searches of the plurality of searches in order of increasing random hit rate taught by Erhard because FDR scores for randomized matches in decoy databases are known to approximate the distribution of scores for incorrect nonrandomized matches, as taught by Hather (p. 2370, col. 1, par. 3), and it is considered that one of ordinary skill in the art would have recognized the predictable result of searching the most likely categories for the spectrum first. The motivation would have been to avoid identifying incorrect peptides or proteins, as taught by Hather (p. 2369, col. 2, par. 2).
Regarding claim 42, Erhard in view of Hather teaches claims 26-27 and 207. Claim 42 further adds that the one or more databases comprises a human genome database, and that the plurality of searches comprise the following searches ordered sequentially in a workflow as follows: a linear human proteome search for the peptide sequence within the expanded human proteome database; a linear human genome search of translations of the human genome database; a linear mismatch search for peptides having a mismatch to the peptide sequence within the expanded human proteome database; and a cis-spliced search, within the expanded human proteome database, for peptide fragments that can be cis-spliced to match the peptide sequence.
Erhard teaches searching the 6-frame translation of the genome (p. 1019, col. 1, par. 3). Erhard teaches categorizing the peptide spectra according to the priority list of CDS (i.e., linear human proteome search) > 5’-UTR > Off-Frame > Frameshift > 3’-UTR > ncRNA > Substitution (i.e., linear mismatch search) > Intronic > Intergenic (i.e., linear human genome search) > PCPS (p. 1019, col. 1, par. 4 through col. 2, par. 1). Erhard teaches that the PCPS peptide database includes cis-spliced peptides (i.e., cis-spliced search) (p. 1020, col. 2, par. 3). Although Erhard does not teach the same prioritization as instantly claimed, it would have been obvious to one of ordinary skill in the art to modify the priority list based on the identified false discovery rate, as discussed above. It would have been obvious to perform the searches of the plurality of searches in order of increasing random hit rate taught by Erhard because FDR scores for randomized matches in decoy databases are known to approximate the distribution of scores for incorrect nonrandomized matches, as taught by Hather (p. 2370, col. 1, par. 3), and it is considered that one of ordinary skill in the art would have recognized the predictable result of searching the most likely categories for the spectrum first. The motivation would have been to avoid identifying incorrect peptides or proteins, as taught by Hather (p. 2369, col. 2, par. 2).
Regarding claim 43, Erhard in view of Hather teaches claims 26-27, 207, and 42. Claim 43 further adds that the one or more databases comprises a non-endogenous proteome database comprising computer-readable representations of proteins translated from RNA from non- endogenous organisms and/or proteins synthesized by non-endogenous organisms, that the plurality of searches further comprises a linear non-endogenous search for the peptide sequence within the non-endogenous proteome database, and that the linear non-endogenous search is ordered sequentially in the workflow after the linear mismatch search and before the cis-spliced search, which Erhard does not teach.
However, Hather teaches analyzing data sets of N2 Caenorhabditis elegans mitochondria and a protein standard mixture of 54 proteins (BIATECH-54 mix), consisting of 38 Shewanella oneidensis proteins plus 16 proteins from other species (p. 2370, col. 2, par. 2). Hather teaches searching the datasets against a database of known contaminants and a decoy database of Rhodobacter sphaeroides appended to increase its complexity (i.e., a linear non-endogenous search within a database of proteins synthesized by non-endogenous organisms) (p. 2370, col. 2, par. 4). Hather does not teach performing searching in a specific order.
However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, Erhard and Hather because each reference discloses methods for determining false discovery rates using randomized or decoy databases. The motivation to include proteins of non-endogenous organisms would have been to increase the complexity of the database, as taught by Hather (p. 2370, col. 2, par. 4). Further, it would have been obvious to perform the searches of the plurality of searches in order of increasing random hit rate taught by Erhard because FDR scores for randomized matches in decoy databases are known to approximate the distribution of scores for incorrect nonrandomized matches, as taught by Hather (p. 2370, col. 1, par. 3), and it is considered that one of ordinary skill in the art would have recognized the predictable result of searching the most likely categories for the spectrum first. The motivation would have been to avoid identifying incorrect peptides or proteins, as taught by Hather (p. 2369, col. 2, par. 2).
Regarding claim 45, Erhard in view of Hather teaches claims 26-27, 207, and 42. Claim 45 further adds halting advancement of the workflow to a subsequent search of the plurality of searches when the putative source is determined for the peptide sequence.
Erhard does not teach halting advancement of the workflow to a subsequent search as instantly claimed. However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify, in the course of routine experimentation and with a reasonable expectation of success, the method of Erhard. It would have been obvious to perform the searches of the plurality of searches in order of increasing random hit rate taught by Erhard because FDR scores for randomized matches in decoy databases are known to approximate the distribution of scores for incorrect nonrandomized matches, as taught by Hather (p. 2370, col. 1, par. 3), and it is considered that one of ordinary skill in the art would have recognized the predictable result of searching the most likely categories for the spectrum first. The motivation would have been to avoid identifying incorrect peptides or proteins, as taught by Hather (p. 2369, col. 2, par. 2). It would have further been obvious to not continue on to the next database search because Erhard teaches assigning the category based on the priority order. One of ordinary skill in the art would recognize that it would not matter whether the subsequent searches were performed because the category had already been assigned once a match was found in a higher priority database.
Regarding claim 46, Erhard in view of Hather teaches claim 26. Claim 46 further adds that the peptide sequence comprises at least one ambiguous residue, generating a plurality of permutated peptide sequences each comprising a potential residue for each of the at least one ambiguous residue such that the plurality of permutated peptide sequences comprises leucine and isoleucine as potential residues, and determining the putative source of the peptide sequence such that the putative source is identified by a search of the plurality of searches having the lowest random hit rate for which a match of any of the plurality of permutated peptide sequences is found.
Erhard inserting all possible combinations of isobaric leucine and isoleucine (i.e., ambiguous residues) into the search keywords for the de novo peptide candidates (p. 1019, col. 2, par. 3).
Regarding claim 50, Erhard in view of Hather teaches claim 26. Claim 50 further adds that the peptide sequence is a de novo peptide sequence determined via mass spectrometry.
Erhard teaches de novo peptide sequencing to produce peptide sequences for subsequent database searches (p. 1019, col. 1, par. 2 through col. 2, par. 3).
B. Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Erhard in view of Hather, as applied to claims 26-27 above, and in further view of Othoum et al. (NAR Cancer, 2020, 2(3):1-11; newly cited).
Regarding claim 28, Erhard in view of Hather teaches claims 26-27. Claim 28 further adds that the expanded human proteome database comprises computer-readable representations of translations from micro RNAs, computer-readable representations of translations from long non-coding RNAs, and/or computer-readable representations of translations of human endogenous retroviruses, which Erhard does not explicitly teach.
However, Othoum discloses a comprehensive integrative analysis of mass spectrometry-based proteomic and transcriptomic sequencing data from >900 patients across nine cancer types to discover long noncoding RNAs encoding peptides (abstract). Othoum teaches constructing the database for the proteogenomic search using three-frame translation of annotated long noncoding RNAs (p. 2, col. 1, par. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, Erhard in view of Hather with Othoum because each Erhard and Othoum each teach methods for identifying peptides encoded in RNA sequences. The motivation to examine long noncoding RNA would have been to identify micropeptides encoded by short open reading frames in long noncoding RNA, as taught by Othoum (p. 1, col. 1, par. 1 through col. 2, par. 3).
C. Claims 40-41 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Erhard in view of Hather, as applied to claims 26-27 and 207 above, and in further view of Ruggles et al. (Molecular & Cellular Proteomics, 2016. 15(3):1060-1071; newly cited).
Regarding claim 40, Erhard in view of Hather teaches claims 26-27. Claim 40 further adds that the plurality of searches comprises a trans-spliced search, within the expanded human proteome database, for computer-readable representations of peptide fragments that can be trans-spliced to match the peptide sequence, which Erhard and Hather do not teach.
However, the prior art to Ruggles discloses a proteogenomic data integration tool (QUILTS) to illustrate protein variant discovery using whole genome, whole transcriptome, and global proteome datasets generated from a pair of luminal and basal-like breast cancer-patient-derived xenografts (PDX) (abstract). Ruggles teaches database construction involving a fusion file containing all predicted fusion genes (i.e., trans-spliced) for peptide searching (p. 1061, col. 2, par. 4; p. 1062, col. 2, par. 2; Fig. 1H).
Regarding claim 44, Erhard in view of Hather teaches claims 26-27, 207, and 42. Claim 44 further adds that the plurality of searches further comprises a trans-spliced search within the expanded human proteome database, for peptide fragments that can be trans-spliced to match the peptide sequence, and that the trans-spliced search is ordered sequentially in the workflow after the cis-spliced search, which Erhard does not teach.
However, Ruggles teaches database construction involving a fusion file containing all predicted fusion genes (i.e., trans-spliced) for peptide searching (p. 1061, col. 2, par. 4; p. 1062, col. 2, par. 2; Fig. 1H). Ruggles does not teach performing the searches in a particular order as claimed.
However, it would have been obvious to perform the searches of the plurality of searches in order of increasing random hit rate taught by Erhard because FDR scores for randomized matches in decoy databases are known to approximate the distribution of scores for incorrect nonrandomized matches, as taught by Hather (p. 2370, col. 1, par. 3), and it is considered that one of ordinary skill in the art would have recognized the predictable result of searching the most likely categories for the spectrum first. The motivation would have been to avoid identifying incorrect peptides or proteins, as taught by Hather (p. 2369, col. 2, par. 2).
Regarding claim 41, Erhard in view of Hather and Ruggles teaches claims 26-27, 207, 42, and 44. Claim 41 further adds that the putative source is determined to be unidentified when the trans-spliced search does not find computer-readable representations of peptide fragments that can be trans-spliced to match the peptide sequence.
Erhard in view of Hather and Ruggles is considered to teach performing a plurality of searches, including the trans-spliced search, in an a specific order, as described above in regards to claim 44. Erhard further teaches discarding spectra if the best candidate for the de novo peptide sequencing was not found in the sequence database (p. 1019, col. 2, par. 2), which reads on determining the putative source to be unidentified as instantly claimed.
Regarding claims 40-41 and 44, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, Erhard in view of Hather with Ruggles because each reference discloses methods for determining peptides identities. The motivation to include a trans-spliced search would have been to determine whether polymorphisms, mutations, and splice variants, including fusions, in cancer cells are translated, as taught by Ruggles (abstract).
Conclusion
No claims are allowed.
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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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