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 .
Priority
This application was filed on and is a U.S. national Stage application under 35 U.S.C. 371 of International Patent Application No. PCT/EP2021/080219 filed 10/29/2021, which claims the benefit of the priority of European Patent Application No. EP 20204915.1 filed 10/30/2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Claims 3, 4-5, 8, 10-11, and 13 are withdrawn from further consideration pursuant to 37 CFR1.142(b) as being drawn to a nonelected Group II and III or based on the elected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/12/2026. Applicant’s election without traverse of Group I drawn to a method for site-selective modification, in the reply filed on 01/12/2026 is acknowledged.
Applicant further elects the species of acylation tag HHHKHHHHHH, the acylating reagent
4-methoxylphenyl-2-azidoacetate. As a result, claims 3, 4-5, 8 are withdrawn.
Claim Status
Claims 1-11, 13, and 16-17 are pending. Claims 3, 4-5, 8, 10-11, and 13, are withdrawn. Claims 12, 14-15 are canceled. Claims 16-17 are new. Claims 1-2, 6-7, 9, and 16-17 are being examined on the merits in this office action.
Claim Objections - Withdrawn
The objection of claims 1 and 9 is withdrawn in view of the amended claims.
Claim Rejections - 35 USC § 112 - Withdrawn
The rejection of claims 7 and 9 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amended claims.
Claim Rejections - 35 USC § 103 – Maintained
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 1-2, 6-7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Usera et al. (WO2015200080A1 – hereinafter “Usera”), in view of Tavare et al. (J. of Inorg. Biochem. 114 (2012) 24–27) and Maldonado et al. (Nat. Commun. 2018, 7; 9(1):3307).
Usera teaches a method for modifying a target protein or a target peptide comprising contacting the protein with an acylating compound, wherein the compound comprises histidine (Pages 1-3, 18). Usera teaches that the histidine tag comprises 1 to 10 histidine (page 19, 1st paragraph).
Usera does not teach that the acylation tag has a single lysine or that the acylation tag is HHHKHHHHHH, and that the acylating reagent is 4-methoxylphenyl-2-azidoacetate.
Examiner notes that the use of acylation tags that comprises lysine and at least three histidine residues is known in the art and the use acylating reagents such as 4-methoxylphenyl-2-azidoacetate is known in the art as taught by Tavare and Maldonado.
Tavare teaches site specific modification using a histidine tag, wherein the histidine tag is located in the C-terminus of the protein (Abstract), wherein the histidine tag includes peptides such as CKLAAALEHHHHHH (Abstract). Examiner notes that the tag of Tavare comprises a single lysine and at least 3 histidine residues.
Regarding the acylation reagent, Maldonado teaches a method of selective acylation of proteins or peptides and that the acylation tag had a Lys was placed C-terminal of the GHHHHHH and that the modification is at the neighboring Lys Nε-amine (Page 4, left col., line 1-7). Maldonado teaches the use of acylating reagent 4-methoxyphenyl 2-azidoacetate (18), and that the reagent is stable and could introduce with high selectivity an azido moiety at 4 °C which was particularly attractive feature (Page 8, right col., line 1-5, Page 9, right col., 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Usera with the teachings of Tavare and Maldonado and use the acylating tag taught by Tavare and Maldonado since Maldonado teaches that the tag with a lysine residue gave slightly elevated level of acylation (Page 4, left col. Line 1-4), and that the acylating reagent 4-methoxyphenyl 2-azidoacetate is stable and could introduce with high selectivity an azido moiety at 4 °C which was particularly attractive feature (Page 8, right col., line 1-5, Page 9, right col., 2nd paragraph). One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in using the acylating tag and reagent taught by Tavare and Maldonado since Maldonado teaches using the acylating reagent 4-methoxyphenyl 2-azidoacetate introduces high selectivity azido moiety at 4 °C which was particularly attractive feature (Page 8, right col., line 1-5, Page 9, right col., 2nd paragraph). Examiner notes that the disclosures render obvious claim 1.
Regarding claim 2, Maldonado teaches a method of selective acylation of proteins or peptides and that the acylation tag had a Lys was placed C-terminal of the GHHHHHH and that the modification is at the neighboring Lys Nε-amine (Page 4, left col., line 1-7) which is less than 25 amino acids. Further, Tavare teaches wherein the histidine tag includes peptides such as CKLAAALEHHHHHH (Abstract). It would have been obvious to one of ordinary skill in the art to modify the method taught by Usera with the teachings of Tavare and Maldonado and use the acylating tag taught by Tavare and Maldonado since Maldonado teaches that the tag with a lysine residue gave slightly elevated level of acylation (Page 4, left col. Line 1-4),
Regarding claims 6-7, Maldonado teaches that the method comprises introducing biotin or fluorophore to aid in identification and characterization (Abstract; Page 4, left col., 2nd paragraph; Page 5, left col., last line). It would have been obvious to attach a bio interactive agent such as biotin and fluorophore to aid in identification and characterization of the protein.
Regarding claim 9, Maldonado teaches the use of acylating reagent 4-methoxyphenyl 2-azidoacetate (18), and that the reagent is stable and could introduce with high selectivity an azido moiety at 4 °C which was particularly attractive feature (Page 8, right col., line 1-5, Page 9, right col., 2nd paragraph). Maldonado teaches that the acylating reagent 4-methoxyphenyl 2-azidoacetate (18), has the structure
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which reads on claim 9, wherein R2 is methoxy, and E2 is an azide. One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in using the acylating tag and reagent taught by Maldonado since Maldonado teaches using the acylating reagent 4-methoxyphenyl 2-azidoacetate introduces high selectivity azido moiety at 4 °C which was particularly attractive feature (Page 8, right col., line 1-5, Page 9, right col., 2nd paragraph).
Response to Arguments
Applicant's arguments filed 04/28/2026 have been fully considered but they are not persuasive.
Applicant Arguments
Applicant argues that is no disclosure in Usera of a single lysine residue being part of the acylation tag, only that the histidine tag can further comprise methionine and that there is no disclosure in Usera that it is the lysine being modified at the s-amine upon contact with the acylating reagent. Applicant argues that Usera teaches the modification only at the N-terminus.
Applicant argues that Tavare does not use an acylating reagent and hence there is no disclosure that a target protein or peptide, upon contact with an acylating reagent, can become modified at the s-amine of the lysine residue of the tag.
Applicant further argues that Maldonado teaches N-terminal modifications, and the teachings of Maldonado do not encourage the skilled person to apply an acylation tag comprising a single lysine residue and at least three histidine residues for facilitating site-selective modification at the C-terminal or internally of a target protein.
Examiner’s Response
The arguments presented above have been fully considered but are unpersuasive.
Examiner notes that site -selective modification of proteins by contacting the protein with an acylation tag in the presence of an acylation reagent is known in the art as taught by Usera. Additionally, an acylation tag comprising one lysine and three histidine residues is known in the art as taught by both Tavare and Moldonado. Additionally, the use on an acylation reagent is taught by Moldonado. Specifically, Maldonado teaches a method of selective acylation of proteins or peptides and that the acylation tag had a Lys was placed C-terminal of the GHHHHHH and that the modification is at the neighboring Lys Nε-amine (Page 4, left col., line 1-7) and teaches the use of acylating reagent 4-methoxyphenyl 2-azidoacetate (Page 8, right col., line 1-5, Page 9, right col., 2nd paragraph). Applicant argues that the references do not teach internal or C-terminal acylation. However, Tavare teaches acylation tag at the C-terminus.
Examiner notes that the rejection is based on the combined teachings of Usera, Tavare and Moldonado. Thus, in response applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Usera already teaches site -selective modification of proteins by contacting the protein with an acylation tag in the presence of an acylation reagent. Usera does not teach the specific acylation tag or reagent, but these are known in the art as taught by the secondary references. One of ordinary skill in the art would be motivated to use other types of acylation tags or reagents to modify the protein either at the C or N terminus. Combining references according to the known methods to yield predictable results amounts to no more than combining prior art elements i.e. acylation tag in the presence of an acylation reagent to modify the protein. These elements have already been taught in the art to be combined as taught by Usera. A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950) See MPEP 2143.02.
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Examiner notes that when the teachings of the cited references are combined, the invention is obvious.
Claim Rejections - 35 USC § 103 – New
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 16 is rejected under 35 U.S.C. 103 as being unpatentable over Usera et al. (WO2015200080A1 – hereinafter “Usera”), in view of Tavare et al. (J. of Inorg. Biochem. 114 (2012) 24–27) and Maldonado et al. (Nat. Commun. 2018, 7; 9(1):3307) as applied to claim 1 above, and further in view of Masumi et al. (WO2011024887A1 – hereinafter “Masumi”).
The teachings of Usera, Tavare, and Maldonado are disclosed above and incorporated herein by reference.
Usera does not teach the acylation tags recited in claim 16.
Masumi teaches addition of histidine tags on either the N or C terminus of proteins and that the His6 tag has the amino acid sequence Lys-His-His-His-His-His-His (See Example 7 and [0093]). Examiner notes that the sequence of Masumi reads on SEQ ID NO: 6.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Usera and use other histidine tags such as the one taught by Masumi so as to modify the protein. One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in using other acylating tags as taught by Masumi since Masumi teaches using the tags on the C or N-terminus of the protein for site selective modification. The disclosures render obvious claim 16.
Examiners comment and Allowable subject matter
Claims 1-2, 6-7, 9 and 16 are rejected.
Examiner notes that the instant method wherein the acylation tag is the elected HHHKHHHHHH (SEQ ID NO: 63) is free of prior art. The search was expanded to the genus and the rejection is disclosed above.
Claim 17 recites that the acylation tag is the elected HHHKHHHHHH (SEQ ID NO: 63). Claim 17 is thus objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MERCY H SABILA/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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