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 .
Claim Status
Claims 1-20 are pending.
No claims have been amended.
No claims have been cancelled.
Thus, claims 1-20 represent all claims currently under consideration.
Priority
Domestic Priority data as claimed by Applicant:
This application claims benefit of PRO 63/461,131 (04/21/2023)
Claim Objections
Claim 6 is objected to because of the following informalities:
In line 3, “the first linker arm” should read “the first linker group”.
Appropriate correction is required.
Claim Interpretation
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.
This application includes one or more claim limitations that use the word “means” or “step” but are nonetheless not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph because the claim limitation recites sufficient structure, materials, or acts to entirely perform the recited function. Such claim limitation is: “wherein the MS-cleavable haloacetamide-based cross-linker is configured to specifically interact with cysteine groups for mapping intra-protein interactions in a protein, or inter-protein interactions in a protein complex, or combinations thereof” in claim 1.
Because this claim limitation is not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it is not being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof.
If Applicant intends to have this limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, Applicant may: (1) amend the claim limitation to remove the structure, materials, or acts that performs the claimed function; or (2) present a sufficient showing that the claim limitation does not recite sufficient structure, materials, or acts to perform the claimed function.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8 and 17-20 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.
Claim 1 recites a genus comprising a sulfoxide group, and claims 1-2 recite the phrase “one or more MS-cleavable bonds” in line 4 and lines 1-2, respectively. However, the instant specification indicates that C-S bonds adjacent to centrally located sulfoxide group are MS-cleavable (Specification; pages 3, 0007-0008, lines 4-5, DBrASO structure and Formula I structure), and sulfoxides by definition comprise two C-S bonds. Therefore, it is unclear how one could possess a sulfoxide with only one MS-cleavable bond as indicated in claims 1-2, and this ambiguity renders the instant claims indefinite.
Regarding claims 2-8 and 17-20, these dependent claims do not resolve the indefiniteness of claim 1 detailed above.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (US 2021/0253524 A1; published 08-19-2021; equivalent of US 11,603352 B2; IDS of 05-19-2026), in view of S. A. Block (“Expansion of Collision Induced Dissociation-Cleavable Protein Cross-linkers for Simplified Tandem Mass Spectrometric Analysis”; PhD Dissertation; published 2019).
Regarding claims 1-4, 6-7, and 9-10, Huang teaches the synthesis of a sulfoxide-containing homobifunctional cysteine-reactive mass spectrometry-cleavable cross-linker for mapping intra-protein interactions in a protein and inter-protein interactions in a protein complex or a combination thereof. The MS-cleavable cross-linker comprises at least one central sulfoxide group and two symmetric collision-induced dissociation (CID) cleavable bonds on the spacer arm, wherein each of the two CID cleavable bond is a C-S bond adjacent to the at least one central sulfoxide. Huang further teaches wherein the MS-cleavable linker bis-maleimide sulfoxide (BMSO), comprising the structure (Abstract; 0004, 0006-0007, 0011, 0132-0133; claims 1, 5-6, and 9; Figure 1):
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Huang does not teach a mass spectrometry (MS)-cleavable haloacetamide-based cross-linker comprising one or more haloacetamide groups, wherein the MS-cleavable haloacetamide-based cross-linker is configured to specifically interact with cysteine groups, as recited in instant claim 1.
Furthermore, although the structure of BMSO taught by Huang teaches the sulfoxide and L1/L2 linker groups connected by MS-cleavable bonds in a manner consistent with Formula (I) of instant claim 9, Huang does not teach a mass spectrometry (MS)-cleavable haloacetamide-based cross-linker wherein X1 and X2 are independently haloacetamide groups, as recited in the instant claim.
However, Block teaches the synthesis and application of collision-induced (CID)-cleavable protein cross-linkers, including bismaleimide sulfoxide (BMSO), to facilitate the identification of cysteine-cross-linked peptides. These linkers were used to study protein complexes by mapping protein-protein interactions (PPIs). The BSMO cross-linker is expected to produce intralink and interlink-modified peptides, and Black demonstrates the utility of BMSO by MSn analysis of representative BSMO-interlinked peptides of bovine serum albumin (BSA). Of particular note, Block teaches cysteine residue reactivity with maleimide and haloacetamide containing compounds, and that both of these functional groups are sufficient electrophiles for tagging cysteine residues (Abstract, page xv, paragraph 1; page 2, paragraph 4; page 3, paragraph 1 and Figure 1-1; page 4, paragraphs 2-4; page 53, Scheme 3-1; page 54, paragraphs 1-2; page 61, Figure 3-3; page 64, paragraph 1):
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The prior art as taught by Huang and Block are analogous because they reside in the closely overlapping technical field of MS-cleavable cross-linkers comprising a single, centrally located sulfoxide group and configured to specifically interact with cysteine groups for mapping intra-protein and/or inter-protein interactions in a protein complex, in a manner consistent with the instantly claimed invention. Furthermore, the teachings of Block inform the skilled artisan that maleimide and haloacetamide functional groups are both competent electrophiles for tagging cysteine residues. As such, the skilled artisan would be sufficiently motivated to substitute the maleimide functional group of the BMSO cross-linker of Huang and Block with a haloacetamide functional group as taught by Block to pursue an alternative cysteine-reactive cross-linker for mapping protein-protein interactions with a reasonable expectation of success:
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Such an endeavor would result in the simple substitution of one known element for another to obtain predictable results, as described in MPEP § 2143(I)(B).
Further regarding claims 2-4, the haloacetamide-based crosslinker of Huang in view of Block shown above comprises two MS-cleavable C-S bonds adjacent to the single, centrally located sulfoxide group, in a manner consistent with instant claim 2; wherein the crosslinker has 2 terminal haloacetamide groups that are located at an equal distance to the single, centrally located sulfoxide group, in a manner consistent with instant claim 3; and wherein the haloacetamide group has a structure of
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wherein R1 is halo and R2-R3 are H, in a manner consistent with instant claims 4 and 10.
Further regarding claims 6-7, the haloacetamide-based crosslinker of Huang in view of Block shown above comprises a first and second linker group, wherein one end of the first/second linker groups are connected to the central sulfoxide group and the other end of the first/second linker groups are connected to a terminal haloacetamide group, and wherein the first/second linker groups comprise identical functional groups and are symmetric, as recited in the instant claims.
Further regarding claim 9, the haloacetamide-based cross-linker of Huang in view of Block detailed above resides within the genus of Formula I of claim 9 when X1 and X2 are haloacetamide groups, L1 and L2 are –CH2CH2-CONH-CH2CH2– linker groups, and the C-S bonds adjacent to the sulfoxide groups are MS-cleavable.
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the maleimide functional groups of the BMSO cross-linker of Huang and Block with haloacetamide functional groups as taught by Block to arrive at the invention of claims 1-4, 6-7, and 9. The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, an alternative cysteine-reactive cross-linker for mapping protein-protein interactions, as described above.
Regarding claims 5 and 11, the skilled artisan could arrive at a MS-cleavable haloacetamide-based cross-linker wherein R1 is Br and R2-R3 are H with a reasonable expectation of success based on the genus of Huang in view of Block detailed above (wherein X = halogen).
Regarding claims 8 and 15-16, the haloacetamide-based cross-linker of Huang in view of Block detailed above comprises L1 and L2 linker structures that correspond to –CH2CH2-CONH-CH2CH2– linker groups as detailed above.
Huang and Block do not explicitly teach a compounds corresponding to the structure of DBrASO as recited in claim 8; wherein L1 and L2 are selected from
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, as recited in claim 15, and a compound corresponding to the genus of claim 16.
However, Huang does teach structurally similar MS-cleavable crosslinkers DSSO and DHSO:
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wherein the reactive moieties (i.e., N-O succinimide and amine functional groups, respectively) are directly attached to the terminal ends of the linker chains without any additional carbon spacers, in a manner consistent with the L1/L2 structures
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of instant claim 15 (Figure 1A-1B).
Huang further teaches that considering the spacer-arm length of BMSO (24.2 Å) and the distances contributed by the cysteine side chains (2.8 Å), the theoretical upper limit for the Cα-Cα distances between the BMSO-cross-linked cysteine residues is ~ 45 Å. In studies using BSA as a model protein and using BMSO, DSSO, and DHSO as crosslinkers, a large portion of the identified cysteine cross-links obtained from BMSO correspond to residues with Cα-Cα distances over 30 Å which are more likely to be missed with cross-linkers containing shorter spacer arms (i.e., DSSO and DHSO). Although BMSO appears to obtain more contacts in the center regions of BSA, DSSO and DHSO cross-linking have broader coverage of various regions, including both termini (0156-0157).
Thus, the skilled artisan would recognize from the teachings of Huang that the spacer arm length of the MS-cleavable cross-linkers impact the region and extent of protein labeling. Furthermore, cross-linkers possessing a two carbon spacer between the terminal amide moiety and the reactive group (as in BMSO) and cross-linkers possessing no spacer between the terminal amide moiety and the reactive group (as in DHSO) are known in the cited prior art to show differential protein labeling characteristics. In addition, the structurally similar, albeit shorter DSSO and DHSO cross-linkers of Huang with no terminal carbon spacer groups demonstrate broader coverage of protein labeling compared to BMSO. Therefore, based on these teachings the skilled artisan could arrive at the haloacetamide-based cross-linker of Huang in view of Block detailed above, wherein L1 and L2 are
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as recited in claim 15 with a reasonable expectation of success through means of routine optimization that is not inventive in nature. See MPEP § 2144.05(II). This optimization would correspond to the following structure:
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This optimized genus of Huang in view of Block encompasses the structure of claim 8 when X = Br and the genus of claim 16 when X is Cl, Br, or I. Therefore, the skilled artisan could arrive at the invention of claims 8 and 15-16 with a reasonable expectation of success based on the optimized genus of Huang in view of Block detailed above
Regarding claims 12-14, the haloacetamide-based cross-linker of Huang in view of Block detailed above comprises L1 and L2 linker structures that correspond to
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wherein z1 and z2 is 2.
Regarding claims 17 and 19, Huang teaches a method for mapping intra-protein interactions in a protein, inter-protein interactions in a protein complex or a combination thereof. The method comprises: providing the MS-cleavable cross-linker; forming a cross-linked protein or protein complex by cross-linking the protein or the protein complex with the MS-cleavable cross-linker; forming one or more peptide fragments that are chemically bound to the MS-cleavable cross-linker by digesting the cross-linked protein or protein complex with an enzyme; and identifying the one or more peptide fragments using tandem mass spectrometry (MSn), thereby mapping intra-protein interactions in a protein and inter-protein interactions in a protein complex. Huang further teaches wherein the cross-linking the protein or the protein complex with the MS-cleavable cross-linker occurs by conjugation of cysteines, and the MS-cleavable cross-linking agent is BMSO.
In one embodiment, to evaluate BMSO cross-linking of proteins, bovine serum albumin (BSA) was used as a model protein. BMSO cross-linking of BSA was optimized by titrating various ratios of protein to cross-linker concentrations, temperature and reaction time. The resulting cross-linked proteins were separated by SDS-PAGE, digested and subjected to LC-MSn analysis. A total of 41 unique BMSO inter-linked peptides of BSA were identified by LC-MSn analysis, representing 38 unique C—C linkages (0021-0022, 0026, 0028, and 0153-0155; Table 1; claims 10-11 and 15).
Further regarding claim 19, the method of Huang was successfully employed to map the human COP9 signalosome (CSN) interaction topology by mapping PPIs within two CSN complexes that comprise eight or nine protein subunits, respectively. Following treatment with cross-linker, the resulting cross-linked proteins were digested by lys-C and trypsin, cross-linked peptides were enriched from peptide mixtures by size exclusion chromatography (SEC), analyzed by LC-MSn, and identified through database searching and result integration (0095 0129, 0132, 0134, 0139, 0144, and 0203, 0269, 0275, 0282-0285, and 0301; Example 10; claims 16-17 and 20; Figures 12, 18, and 21).
The skilled artisan would recognize the SEC method step used to isolate fractions that are enriched with cross-linked protein fragments or peptides, in a manner consistent with the instant claim. Therefore, based on these teachings and the haloacetamide-based cross-linker of Huang in view of Block detailed above, the skilled artisan could arrive at the methods of instant claims 17 and 19 with a reasonable expectation of success.
Regarding claim 18, Huang teaches that LC-MSn analysis was performed and two different types of acquisition methods were utilized to maximize the identification of BMSO cross-linked peptides, including a top 4 data-dependent MS3 method. MS3 data was further subjected to database searching (0217-0218).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (US 2021/0253524 A1; published 08-19-2021; equivalent of US 11,603352 B2; IDS of 05-19-2026), in view of S. A. Block (“Expansion of Collision Induced Dissociation-Cleavable Protein Cross-linkers for Simplified Tandem Mass Spectrometric Analysis”; PhD Dissertation; published 2019) as applied to claims 1-19 above, and further in view of Jiao et al. (“Two-Dimensional Fractionation Method for Proteome-Wide Cross-Linking Mass Spectrometry Analysis”; Anal. Chem. 2022, 94, 4236-4242; published 03-02-2022; IDS of 05-19-2026, NPL Cite No. 16).
Regarding claim 20, claim 19 is rendered obvious over Huang in view of Block as detailed above.
Although Huang teaches the use of size exclusion chromatography to separate enriched cross-linked protein peptides (0282 and 0301; Example 10), Huang and Block do not explicitly teach using peptide size exclusion chromatography coupled with high pH reverse phase tip fractionation, as recited in claim 20.
However, Jiao teaches that cross-linking mass spectrometry (XL-MS) is an emergent technology for studying protein-protein interactions (PPIs) and elucidating architectures of protein complexes. Jiao further teaches a two-dimensional (2D) separation strategy by integrating peptide size exclusion chromatography (SEC) with tip-based high pH reverse-phase (HpHt) fractionation to expand the coverage of proteome-wide XL-MS analyses. Combined with the MS-cleavable cross-linker DSSO, Jiao teaches the in vitro mapping of PPIs from HEK293 cell lysates with improved identification of cross-linked peptides compared to existing approaches. In addition, Jiao teaches that high pH reverse-phase chromatography has proven effective in reducing sample complexity and enhancing the identification of low-abundance peptides in complex samples for bottom-up proteomic studies. The method developed enables improved peptide separation to expand the dynamic range and can be generalized for cross-linking studies of complex samples (Abstract; page 4237, Col. 1, paragraphs 1-2 and Figure 1; page 4238, Col. 1, paragraph 2).
The methods of Jiao, Huang, and Block are analogous because they reside in the closely overlapping technical field of methods utilizing sulfoxide-containing MS-cleavable cross-linkers, and both Jiao and Huang teach the use of peptide size exclusion chromatography (SEC) for assessing PPIs in protein samples. As such, the skilled artisan would be sufficiently motivated to modify the method of Huang and Block to implement the use of peptide SEC coupled with high pH reverse phase tip fractionation as taught by Jiao to predictably pursue a method that has proven effective in reducing sample complexity and enhancing the identification of low-abundance peptides in complex samples with a reasonable expectation of success. Such an endeavor would result in combining prior art elements according to known methods to yield predictable results, as described in MPEP § 2143(I)(A).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have modified the method of Huang and Block to incorporate the teachings of Jiao to arrive at the claimed invention. The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, a method enables improved peptide separation to expand the dynamic range and has proven effective in reducing sample complexity and enhancing the identification of low-abundance peptides in complex samples, as described above.
Double Patenting Rejections
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 1-7, 9-14, and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-6, and 10-11 of U.S. Patent No. 11,603,352 B2 (IDS of 05-19-2026; hereinafter “patent ‘352”), in view of in view of S. A. Block (“Expansion of Collision Induced Dissociation-Cleavable Protein Cross-linkers for Simplified Tandem Mass Spectrometric Analysis”; PhD Dissertation; published 2019).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-4, 6-7, and 9-10, claim 1 of patent ‘352 teaches an MS-cleavable cross-linker for mapping intra-protein interactions in a protein, inter-protein interactions in a protein complex or a combination thereof, wherein the MS-cleavable cross-linker is BMSO, comprising the structure:
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Patent ‘352 does not teach a mass spectrometry (MS)-cleavable haloacetamide-based cross-linker comprising one or more haloacetamide groups, wherein the MS-cleavable haloacetamide-based cross-linker is configured to specifically interact with cysteine groups, as recited in instant claim 1.
Furthermore, although the structure of BMSO taught by patent ‘352 teaches the sulfoxide and L1/L2 linker groups connected by MS-cleavable bonds in a manner consistent with Formula (I) of instant claim 9, patent ‘352 does not teach a mass spectrometry (MS)-cleavable haloacetamide-based cross-linker wherein X1 and X2 are independently haloacetamide groups, as recited in the instant claim.
These deficiencies are remedied by Block, whose teachings are incorporated from the 103 rejection of claim 1 detailed above.
The prior art as taught by patent ‘352 and Block are analogous because they reside in the closely overlapping technical field of MS-cleavable cross-linkers comprising a single, centrally located sulfoxide group and configured to specifically interact with cysteine groups for mapping intra-protein and/or inter-protein interactions in a protein complex, in a manner consistent with the instantly claimed invention. Furthermore, the teachings of Block inform the skilled artisan that maleimide and haloacetamide functional groups are both competent electrophiles for tagging cysteine residues. As such, the skilled artisan would be sufficiently motivated to substitute the maleimide functional group of the BMSO cross-linker of patent ‘352 and Block with a haloacetamide functional group as taught by Block to pursue an alternative cysteine-reactive cross-linker for mapping protein-protein interactions with a reasonable expectation of success:
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Such an endeavor would result in the simple substitution of one known element for another to obtain predictable results, as described in MPEP § 2143(I)(B).
Further regarding claims 2-4, the haloacetamide-based crosslinker of patent ‘352 in view of Block shown above comprises two MS-cleavable C-S bonds adjacent to the single, centrally located sulfoxide group, in a manner consistent with instant claim 2; wherein the crosslinker has 2 terminal haloacetamide groups that are located at an equal distance to the single, centrally located sulfoxide group, in a manner consistent with instant claim 3; and wherein the haloacetamide group has a structure of
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wherein R1 is halo and R2-R3 are H, in a manner consistent with instant claims 4 and 10.
Further regarding claims 6-7, the haloacetamide-based crosslinker of patent ‘352 in view of Block shown above comprises a first and second linker group, wherein one end of the first/second linker groups are connected to the central sulfoxide group and the other end of the first/second linker groups are connected to a terminal haloacetamide group, and wherein the first/second linker groups comprise identical functional groups and are symmetric, as recited in the instant claims.
Further regarding claim 9, the haloacetamide-based cross-linker of patent ‘352 in view of Block detailed above resides within the genus of Formula I of claim 9 when X1 and X2 are haloacetamide groups, L1 and L2 are –CH2CH2-CONH-CH2CH2– linker groups, and the C-S bonds adjacent to the sulfoxide groups are MS-cleavable.
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the maleimide functional groups of the BMSO cross-linker of patent ‘352 and Block with haloacetamide functional groups as taught by Block to arrive at the invention of claims 1-4, 6-7, and 9. The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, an alternative cysteine-reactive cross-linker for mapping protein-protein interactions, as described above.
Regarding claims 5 and 11, the skilled artisan could arrive at a MS-cleavable haloacetamide-based cross-linker wherein R1 is Br and R2-R3 are H with a reasonable expectation of success based on the genus of patent ‘352 in view of Block detailed above (wherein X = halogen).
Regarding claims 12-14, the haloacetamide-based cross-linker of patent ‘352 in view of Block detailed above comprises L1 and L2 linker structures that correspond to
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wherein z1 and z2 is 2.
Regarding claim 17, claim 5 of patent ‘352 teaches a method for mapping intra-protein interactions in a protein, inter-protein interactions in a protein complex or a combination thereof, the method comprising: providing the MS-cleavable cross-linker of claim 1, forming a cross-linked protein or protein complex by cross-linking the protein or the protein complex with the MS-cleavable cross-linker; forming one or more peptide fragments that are chemically bound to the MS-cleavable cross-linker by digesting the cross-linked protein or protein complex with an enzyme; and identifying the one or more peptide fragments using tandem mass spectrometry (MSn), thereby mapping intra-protein interactions in a protein and inter-protein interactions in a protein complex. In addition, claim 6 of patent ‘352 teaches wherein the cross-linking the protein or the protein complex with the MS-cleavable cross-linker occurs by conjugation of cysteines. Furthermore, claim 10 of patent ‘352 teaches a method for cross-linking mass spectrometry (XL-MS) for identifying one or more cross-linked peptides obtained from one or more cross-linked proteins, comprising MSn analysis to identify the one or more cross-linked peptides, and claim 11 of patent ‘352 teaches wherein the cross-linking the protein or the protein complex with the MS-cleavable cross-linker occurs by conjugation of cysteines.
Conclusion
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/D.R./Examiner, Art Unit 1692
/AMY C BONAPARTE/Primary Examiner, Art Unit 1692
