Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The Applicants’ Amendment to the Claims filed on November 20, 2025.
Claims 1-78, 82-107, 109-112, 115-132, 134-137, and 141-153 are cancelled.
Claims 79-81, 108, 113-114, 133, 138-140, and 154-161 are pending.
Claims 79-81, 108, 113-114, and 155-158 are withdrawn.
Claims 133, 138-140, 154, and 159-161 are under examination.
This US18/349,609 filed on 07/10/2023 which is a CON of 16/366,908 filed on 03/27/2019 (now US Patent 11,731,982) which is a DIV of 15/390,820 filed on 12/27/2016 which is a DIV of 13/881,518 filed on 09/26/2013 (now US Patent 9,567,346) which is a 371 of PCT/US2011/058455 filed on 10/28/2011 claims US priority benefit of US Provisional Applications 61/510,949 filed on 07/22/2011, 61/501,500 filed on 06/27/2011, 61/495,070 filed on 06/09/2011, and 61/408,210 filed on 10/29/2010.
Election/Restrictions
Applicant’s election without traverse of Invention Group III (e.g., claims 133, 138-140, 154-156, and 159-161) in the reply filed on 02/28/2025 is as previously acknowledged. Applicant’s election without traverse of the species: A) X is O; B) R1 is H (non-elected species is R1 is a derivative group); C) R2 is a derivative group (non-elected species is R2 is H); D) Y is absent (non-elected species is Y is O); and
E) L is a linker (non-elected species is L is absent), in the reply filed on 05/09/2025 is as previously acknowledged.
Response to Amendment
Rejections made in the previous office action and not repeated in this office action are withdrawn in view of the Applicants’ Amendment to the Claims filed on November 20, 2025.
Claim Rejections - 35 USC § 103 -updated for amendment
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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.
Claims 133, 138-140, 154, and 159-161 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sachon et al “Analogs of Substance P modified at the C-terminus which are both agonist and antagonist of the NK-1 receptor depending on the second messenger pathway” J. Peptide Res. v59 2002 pages 232-240; published 10/09/2008), in view of Hirsch et al “Easily reversible desthiobiotin binding to streptavidin, avidin, and other biotin-binding proteins: uses for protein labeling, detection, and isolation” (Analytical Biochemistry v308 2002 pages 343-357), in further view of Slavoff et al in “Expanding the Substrate Tolerance of Biotin Ligase through Exploration of Enzymes from Diverse Species” (J. AM. CHEM. SOC. Vol 130, No.4, 2008: See STIC structure Result 3 of 19 pages 121-123) or in view of Morocho et al “Novel Biotin Phosphoramidites with Super-Long Tethering Arms” (Nucleosides Nucleotides Nucleic Acids 2003 pages 1439-1441: See STIC structure Result 4 of 19 pages 123-124) or in view of Allart et al (See STIC structure Result 5 of 19 pages 124-125 showing species with Linker is absent). This is a new grounds of rejection.
Regarding claim 133, Sachon et al discloses a method of labeling a protein, comprising the steps of:
a. providing a biotin derivative of instant Formula I;
b. providing a sample comprising a protein comprising a complementary group capable of reacting with a reactive group of position R3 of the biotin derivative; and
c. contacting the biotin derivative with the sample to provide a biotin derivative-labeled protein.
For example, regarding claim 133, part (a), Sachon et al teach a Bapa compound (i.e., biotinyl sulfone-5aminopentanoic acid) (see figure 1 on page 234 & just below).
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Thus, the Bapa formula of Sachon et al meets the limitation of instant Formula (I):
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wherein:
X is O; R1 is selected from H and a derivative group; R2 is selected from H and a derivative group; Y is O or absent; L is absent or is a linker; R3 is a reactive group;
wherein at least one of R1 and R2 is H.
Regarding the compound of formula I, Sachon et al teach Bapa (figure 1 on page 234) which is of instant formula I where X is O, R1 and R2 are H, Y is O, and L-R3 is NH(CH2)4COOH where COOH is the reactive group.
Regarding claim 133, Sachon et al expressly teach Bapa and the incorporation of Bapa into peptides (abstract and Table 3 on page 237 for example). Further, Sachon et al teach that the compound was introduced into substance P sequences (abstract on page 232). Sachon et al teach that Substance P is H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. (See Abstract). Sachon teach the formula of peptides is Z-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe8-Gly9-Leu-X11- CONH2 where Z is Bapa (Table 3 on page 237). Sachon teach the peptide synthesis (page 234 column 1) and specifically teach that boc-5-amino pentanoic acid was coupled with the peptide then with biotinyl sulfone (page 234 last paragraph of column 1).
Regarding claim 133b, Sachon teach providing a sample comprising a protein comprising a complementary group capable of reacting with the reactive group. For example, Sachon teach standard peptide synthesis (page 234 first column) so the -COOH group of Bapa would react with the -NH group of the peptide. In the instant case, there is no explicit definition of ‘protein’ provided in the specification that imposes some lower limit on the size of what is encompassed by the term. Thus the sequences as taught by Sachon meet the limitation of protein.
Regarding claim 133c, Sachon disclose standard peptide synthesis (page 234 first column) so the -COOH group of Bapa would react with the -NH group of the peptide. Sachon teach that boc-5-amino pentanoic acid was coupled with the peptide then with biotinyl sulfone (page 234 last paragraph of column 1).
However, Sachon does not contact with a compound as recited in claim 133 step c, but rather contacts with a precursor (i.e. boc-5-amino pentanoic acid) of Bapa. Sachon differs from the present claims because Sachon teach that boc-5-amino pentanoic acid was coupled with the peptide then with biotinyl sulfone (page 234 last paragraph of column 1). Thus, Sachon does not contact with a compound as recited in claim 133 step c. Sachon contacts with a precursor (i.e. boc-5-amino pentanoic acid) of Bapa. Further, Sachon does not contact with a biotin binding moiety as in claim 138b.
Hirsch teach methods of labeling a protein using biotin-streptavidin.
Regarding to claim 133 step a, Hirsch teach desthiobiotin-X-succinimidyl ester (figure 1c on page 345) which is of formula II of claim 1 where X is O, R1 and R2 are H, L2 is a linker and R3 is a reactive group (i.e. succinimidyl ester, see page 345 last paragraph of column 1). Regarding claim 133 step b, Hirsch specifically teach that the IgG antibody GAM was labeled with desthiobiotin-X-succinimidyl ester (page 348 2ⁿᵈ column 2ⁿᵈ complete paragraph) where desthiobiotin-X-succinimidyl ester reacts with protein amines (page 348 2ⁿᵈ column first complete paragraph). Thus the protein amine is the complementary group. Regarding claim 133 step c, Hirsch teach that the IgG antibody GAM was labeled with desthiobiotin-X-succinimidyl ester (page 348 2ⁿᵈ column 2ⁿᵈ complete paragraph) to prepare a desthiobiotinylated protein (page 348 2ⁿᵈ column 1st section heading under Results).
Further, regarding claims 138-140, and 159-161, Sachon et al discloses the biotinylated derivative Bapa where L-R3 is NH(CH2)4COOH, where COOH is the reactive group.
Regarding claim 138 step a, Hirsch teach Alexa Fluor 488 streptavidin (page 354 2ⁿᵈ paragraph and figure 6 page 352) where Alexa Fluor is a fluorescent dye (page 350 2ⁿᵈ column line 14). Hirsch teach that biotin is known to bind streptavidin (abstract). Regarding claim 138 step b, Hirsch teach that desthiobiotinylated GAM was used to stain alpha-tubulin where the alpha-tubulin was visualized after incubation with Alexa Fluor 488 streptavidin (page 354 2ⁿᵈ paragraph and figure 6 page 352). Regarding claim 139, Hirsch teach Alexa Fluor 488 streptavidin (page 354 2ⁿᵈ paragraph and figure 6 page 352).
Regarding claims 138-140, Hirsch teach the use of Alexa Fluor 488 streptavidin for labelling biotin based compounds (page 354 2nd paragraph and figure 6 page 352). The biotin-binding moiety is streptavidin (instant claim 139) and the detectable moiety is Alexa Fluor 488 which is a fluorescent dye (instant claim 140). (See page 354 2ⁿᵈ paragraph and figure 6 page 352) where Alexa Fluor is a fluorescent dye (page 350 2ⁿᵈ column line 14).
Regarding claims 159-161, Hirsch teach that the high-affinity binding of biotin to streptavidin is specific and almost universally applicable (page 343 abstract and first paragraph). Hirsch teach the technique for protein labeling, detection and isolation (title). Hirsch teach the use of Alexa Fluor 488 streptavidin for detecting biotin based compounds (page 347 2nd column paragraphs 1-3 and page 354 2nd paragraph and figure 6 page 352).
The level of skill in the art was high before the time of the presently claimed invention. In view of Sachon and Hirsch, one of ordinary skill in the art would have been motivated to contact with a compound as recited in claim 133 step c, and contact with a biotin binding moiety as in claim 138b because Sachon expressly teach the incorporation of the Bapa group (abstract and Table 3 on page 237 for example). Further, MPEP 2144.04 IV C recognizes changes in sequence of adding ingredients as a rationale to support an obviousness rejection. In the instant case, Sachon teach that the peptide is contacted with boc-5- amino pentanoic acid which is then coupled with biotinyl sulfone (page 234 last paragraph of column 1). The first reaction involves the reaction of the carboxyl group of boc-5-amino pentanoic acid with the amino group of the peptide. The next reaction involves the amino group of boc-5-amino pentanoic acid which is reacted with the carboxyl group of biotinyl sulfone. As an alternate to make the compound shown in Figure 1 of Sachon, one could combine the 3 relevant compounds (i.e. biotinyl sulfone, 5-aminopentanoic acid and peptide) in a different order (see MPEP 2144.04 IV C). Specifically, 5-aminopentanoic acid is first coupled (via the amino group) with the biotinyl sulfone (via the carboxyl group) which is then reacted with the peptide (via the carboxyl group of the 5-aminopentanoic acid and the carboxyl group of the peptide).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to assemble the Bapa compound taught by Sachon (figure 1 on page 234) and incorporate that compound into the peptides as suggested by Sachon (Table 3 on page 237 for example). One would have had a reasonable expectation of success since the peptide synthesis steps are known (see page 234 first column of Sachon) and the chemistries are known. Specifically the reactive groups of biotinyl sulfone (i.e. carboxyl group), 5-aminopentanoic acid (i.e. amino group and carboxyl group) and of the peptide (i.e. amino group) are known.
Further, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the teachings of Sachon to purify and detect the Bapa group using the techniques taught by Hirsch. Sachon suggests that the Bapa group was introduced for purification purposes and recognize the use of labeling to analyze peptide receptor interactions (page 232 first paragraph and first paragraph of results on page 235 and page 239 24 column). Sachon teach that the use of the biotinyl sulfone group for the labeling procedure was convenient and cheap (first paragraph of results on page 235).
One would have been motivated to do such for the rationale of protein labeling using biotin-streptavidin because Sachon suggests that the biotin derivative Bapa group was introduced for purification purposes and recognize the use of labeling to analyze peptide receptor interactions (page 232 first paragraph and first paragraph of results on page 235 and page 239 2nd column).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the teachings of Sachon to label the protein/polypeptide using the combination of the biotinylated Bapa group of Sachon et al and the techniques of biotin-streptavidin protein-labeling taught by Hirsch et al.
In view of the high skill level in the art before the time of the presently claimed invention it is considered that one of ordinary skill in the art having the Sachon et al and Hirsch et al references would have had a reasonable expectation of success to combine the elements of the cited references to arrive at the presently claimed invention since Hirsch teach that the high-affinity binding of biotin to streptavidin is specific and almost universally applicable (page 343 abstract and first paragraph). Further, Hirsch teach the technique for protein labeling, detection and isolation (title).
However, Sachon and Hirsch do not explicitly disclose the species of claim 133 where X is O and at least one of R1 and R2 is not H. Regarding claim 154, Sachon and Hirsch do not disclose wherein if R1 is H, R2 is a derivative group.
However, the species of biotin derivative of claim 133 where X is O and at least one of R1 and R2 is not H was known in the prior art and disclosed in each of the references of Slavoff et al, Morocho et al, and Allert et al. Further, Morocho et al include a linker whereas Allert et al disclose a species with a linker being absent. Further, regarding claim 154, each of Slavoff et al, Morocho et al, and Allert et al disclose that R1 is H and R2 is a derivative group. Regarding claim 159, Morocho et al discloses a linker.
Slavoff et al in “Expanding the Substrate Tolerance of Biotin Ligase through Exploration of Enzymes from Diverse Species” teach the biotin derivative:
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(See STIC structure Result 3 of 19 pages 121-123).
Morocho et al “Novel Biotin Phosphoramidites with Super-Long Tethering Arms” teach several biotin derivatives of Formula I of instant claim 133, including:
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(See STIC structure Result 4 of 19 pages 123-124).
Allert et al teaches a derivative compound of instant claim 133 where the linker is absent as evidenced by STIC structure result for Allert et al (pages 124-125).
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Allert et al disclose a novel, stable, biotin aldehyde derivative is reported in which the biotin moiety is N1,N3-protected by the allyloxycarbonyl group. Allert et al discloses that the derivative is stable to sodium cyanoborohydride mediated reductive alkylation and is cleaved under mild Pd [0] catalysis. (See abstract, lines 1-4). Allert et al state that “[t]his novel biotin aldehyde should have wide application in avidin- and streptavidin-based detection systems and bioassays”. The derivative is utilized in the synthesis of a biotinylated doxorubicin analogue that retains topoisomerase activity. (See Abstract.).
It would have been obvious to one of ordinary skill in the art at the time the invention was made combine the elements of the cited references of Sachon, Slavoff et al, Morocho et al, and Allert et al with the techniques of biotin-streptavidin protein-labeling taught by Hirsch et al because each of these references are in the field of using biotin derivatives as reactive species.
One would have been motivated to do such for the rationale of protein labeling using biotin-streptavidin because Allert et al state that “[t]his novel biotin aldehyde should have wide application in avidin- and streptavidin-based detection systems and bioassays” and Sachon suggests that the biotin derivative Bapa group was introduced for purification purposes and recognize the use of labeling to analyze peptide receptor interactions (page 232 first paragraph and first paragraph of results on page 235 and page 239 2nd column) and Allert et al disclose a novel, stable, biotin aldehyde derivative is reported in which the biotin moiety is N1,N3-protected by the allyloxycarbonyl group. Allert et al discloses that the derivative is stable to sodium cyanoborohydride mediated reductive alkylation and is cleaved under mild Pd [0] catalysis. (See abstract, lines 1-4).
In view of the high skill level in the art before the time of the presently claimed invention it is considered that one of ordinary skill in the art having the cited references would have had a reasonable expectation of success to combine the elements of the cited references to arrive at the presently claimed invention since Hirsch teach that the high-affinity binding of biotin to streptavidin is specific and almost universally applicable (page 343 abstract and first paragraph). Further, Hirsch teach the technique for protein labeling, detection and isolation (title).
Response to Arguments
The applicants’ response filed on 11/20/2025 has been fully considered but is unpersuasive as it may apply to this updated rejection. The applicants note that base claim 133 is presently amended to recite that X is O and “wherein when X is O, at least one of R1 and R2 is not H, and has deleted the alternative “or Y is O”. Further, the applicants argue that the combination of references of Sachon and Hirsch does not teach or render obvious the species of claim 133 where X is O and at least one of R1 and R2 is not H. The applicants argue that both cited references disclose biotin derivatives wherein R1 and R2 are H. However, this argument is unpersuasive regarding this new grounds of rejection because the species of biotin derivative of claim 133 where X is O and at least one of R1 and R2 is not H was known in the prior art and is disclosed in each of the references of Slavoff et al, Morocho et al, and Allert et al. Morocho et al include a species comprising a linker whereas Allert et al disclose a species absent a linker.
The applicants’ argument is persuasive regarding the species of compounds allowed in the parent US Patent 9,567,346. The present claims are allowable if limited to such compounds.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658