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 .
Status of the application
Receipt of Applicant’s claim amendments and arguments filed 03/23/2026 is acknowledged.
In light of incorporating the SEQ ID NOs, previous Sequence Noncompliance is withdrawn.
In light of claim amendments and applicants arguments, previous 112(d) rejection is withdrawn.
However, applicants arguments for previous 103 rejection are found not persuasive and accordingly, the rejection is maintained and modified to address claim amendments.
Response to Arguments
Applicants main argument is that the cited references do not teach or suggest "adding a CD3l-derived peptide comprising an azide terminal group, wherein the azide terminal group is at the N-terminus or C-terminus of the CD31-derived peptide, and reacting the CD3l-derived peptide comprising the azide terminal group with the alkyne function of the linker of step b."
The rejection [see page 1st paragraph in page 8] says the following:
Alternatively, if applicants think any criticality for azide binding site on the peptide, i.e., C-, or N-terminus or side chain of amino acid on peptide, and that criticality shows unexpected results, applicants are invited to show comparative data, which helps in understanding the claimed invention. Since no such data is shown the specification, and so, this limitation is obvious or trivial, because a skilled person in the art would know suitable binding sites for azide group on the peptide.
It appears that applicants failed to respond to the above reasoning.
Applicants further argue that even if the methods of Kutryk were somehow considered applicable to proteins that are not antibodies (with which Applicant does not agree), the Examiner has provided no reason why one of skill, reading Kutryk, would, in particular, choose any of the sequences in the '741 publication or the '014 publication to substitute for the antibody of Kutryk.
In fact, Kutryk also suggested that cell surface antigens include CD34, CD133, CDw90, CD117, HLA-DR, VEGFR-1, VEGFR-2, VEGFR-3, Muc-18 (CD146), Thy-1, Thy-2, CD130, CD30, stem cell antigen (Sca-1); stem cell factor 1 (SCF/c-Kit ligand), Tie-1, Tie-2, VE-cadherin, P1H12, TEK, CD31, Ang-1, Ang-2, HAD-DR, CD45, CD105, CD14, von Willebrand factor (vWF), and E-selectin etc [see abstract and 0014-0018].
The above includes CD31, in addition to other proteins or peptides. In other words, Kutryk does teach their device is also applicable to other peptides.
So, in light of advantages of device in the teachings of Kutryk, a skilled person in the art would immediately grasp the idea of replacing antibody with other peptides. Moreover, Kutryk does not say that their device does not work with other peptides.
In fact, the above is already mentioned in the rejection, but applicants failed to explain “Why it is not possible to replace antibody in the teachings of Kutryk with other peptides?”.
Applicants are also argue under section ‘No reasonable expectation of success’ that there would simply be no way to attach an azide to the "peptide fragments" in Caliguiri '741 and Caliguiri '536 based on the teachings of Kutryk to arrive at the claimed invention. That is, the combination of Kutryk, Caliguiri '741, and Caliguiri '536 do not teach the skilled person in the art any "suitable binding sites for azide group on the peptide".
Applicants argument simply say ‘no way to attach the peptide….with azide’, but failed to explain why not? Any experimental difficulties in coupling process? Or cited art is not enabled? Applicants are reminded that there is no method step or required conditions in coupling with azide or for the click chemistry etc., in the claims.
Applicants need to explain the reasons, so that claimed invention can be understood.
To avoid delay in the prosecution, applicants agent may have to contact the examiner and get clarifications for above reasoning and pending rejection.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 Kutryk (US 2018/0296732 A1) in view of, Caligiuri (WO2010/000741; see applicants filed IDS dated 05/25/2021), Caligiuri (US 2015/0203536 A1; herein after Caligiuri’536), van Delft (US 2013/0137763 A1), Guida (Biosensors and Bioelectronics, 2018, 100, 298-303), Biswas (ACS NANO, 2015, vol.9, No.10, 9652-9664) and Dunn (WO 2014197547 A1).
For claims 1-3:
Kutryk teaches a method of making a medical device or a substrate coated with polydopamine which is further linked to ligands such as antibodies and/or antibody fragments, wherein the polydopamine coating and the ligands may be linked through a linker such as an organic polymer, wherein the antibodies and/or antibody fragments may specifically bind to a cell surface antigen of endothelial progenitor cells or endothelial cells, wherein the cell surface antigens include CD34, CD133, CDw90, CD117, HLA-DR, VEGFR-1, VEGFR-2, VEGFR-3, Muc-18 (CD146), Thy-1, Thy-2, CD130, CD30, stem cell antigen (Sca-1); stem cell factor 1 (SCF/c-Kit ligand), Tie-1, Tie-2, VE-cadherin, P1H12, TEK, CD31, Ang-1, Ang-2, HAD-DR, CD45, CD105, CD14, von Willebrand factor (vWF), and E-selectin etc [see abstract and 0014-0018].
Kutryk exemplified their method with the following scheme:
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[see Fig. 8C, 0047-0050, 0111, 0117 and 0156].
In the above scheme, the ~square shaped plate (no back slashes) at the bottom is medical device or metallic implant, ~square shaped plate with back slashes is polydopamine layer, wavy line is linker, and Y is protein or antibody comprises azide functional group [see 0154-0156], wherein azide functional group or moiety is introduced at terminal Fc region, after removing terminal galactose sugars [see Fig.8B and 0139].
Kutryk further teaches a step of making polydopamine layer coated on the material surface, as shown below:
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[see Fig. 2A] and a step of addition of functionalized linker on the polydopamine coated surface, as shown below:
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[see Fig. 8A].
Differences between Kutryk and instant claim are as follows:
(i) Kutryk teaches that introducing azide group at terminal Fc region, after removing terminal galactose sugars, but it is not clear whether it is at C-terminus or on the N-terminus amino acid.
(ii) Kutryk is silent on applicants recited sequences, represented by SEQ ID NOs: 2-8, 12-79 and 81).
With regard to (i) of above, Fc region is C-terminus region of antibody. So, azide is expected to be on C-terminus of Fc region, which can be on side chain of C-terminus amino acid or at C-terminus, absent evidence to the contrary.
However, a skilled person in the art that knows that either N- or C-terminus are flexible or hanging amino acids, and so these are suitable for azide coupling and may not affect the overall property of the peptide or protein. Also, coupling at other than N- or C-terminus amino acids may change the protein or peptide conformation, which may effect its property. So, a skilled person can determine suitable coupling sites through a routine experimentation, and therefore, this limitation is obvious.
Alternatively, if applicants think any criticality for azide binding site on the peptide, i.e., C-, or N-terminus or side chain of amino acid on peptide, and that criticality shows unexpected results, applicants are invited to show comparative data, which helps in understanding the claimed invention. Since no such data is shown the specification, and so, this limitation is obvious or trivial, because a skilled person in the art would know suitable binding sites for azide group on the peptide.
With regard to (ii) of above, in fact, applicants already acknowledged that these sequences are known [see page 10, lines 12-18] in WO2010/000741 [see pages 6-10 and 12]. Also, Caligiuri’536 teaches fragments of CD31 see SEQ ID NOs:5-8], and for example, one of the sequence is KWPALFVR [see SEQ ID NO:6], which is identical to applicants SEQ ID NO:6.
Therefore, a skilled person in the art would be motivated to extrapolate teachings of Kutryk to small peptide or other therapeutic peptides, in this case applicants claimed peptides, and arrive at applicants claimed method with a reasonable expectation of success.
Also, the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983).
For claim 4:
Kutryk further teaches that the thickness of polydopamine coating in the range of 1 nm to 100 nm [see 0096].
For claims 5-7:
Kutryk is silent on applicants claimed linker(s) in claims 5-7. However, this can be cured by van Delft, which teaches the following cyclooctyne conjugate and its advantages over the known cyclooctynes in the art,:
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, wherein R is H [see Example 3, 0073, and see its genus in 0081 and subsequent relevant paragraphs].
The above cyclooctyne conjugate reads claimed limitations.
van Delft further teaches that the following cyclooctyne probes for bioorthogonal labeling known in the prior art suffer from several disadvantages:
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, specifically, the synthesis of the currently available probes is lengthy (eight chemical steps for DIFO2, ten steps for DIFO3, nine steps for DIBAC), and/or low-yielding (10% overall for DIBO). Further, the presence of the two benzannulated aryl moieties in DIBO and DIBAC inflicts both serious steric repulsion as well as lipophilic character. The lipophilic character of DIBO and DIBAC may lead to a specific protein binding by van der Waals interactions, which is undesirable. [See 0011-0012 and 0058-0060].
Based on the above, therefore, a skilled person in the art would be motivated to replace cyclooctyne (DIBAC) in the teachings of Kutryk with the cyclooctyne of van Delft, because van Delft teaches that DIBAC has disadvantages as explained in the above paragraph.
For claims 8-9:
Kutryk teach contacting polydopamine coated surface of the material surface with linker [see Fig. 8A]. The linker must be in solution and, stirring and rinsing steps are expected to present in the process of Kutryk because these are common steps in the synthesis process.
For claim 10:
Though Kutryk silent on the thickness of the layer made of the linker, since methodology is similar and the thickness is expected to be in the claimed range, when a skilled person replaces cyclooctyne (DIBAC) in the teachings of Kutryk with the cyclooctyne of van Delft, absent evidence to the contrary.
For claims 11-13:
It appears that the azide group is located at N-terminus of claimed peptide, based on the recited claim language.
Though Kutryk silent on this limitation, however, coupling of azide group at N-terminus of peptides is known in the art and is a common practice, see the cited art below:
Biswas teaches coupling of azide group at N-terminus peptide [see Scheme 1 in page 9654].
Dunn teaches azide group at N-terminus lysine in the following peptide conjugate:
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[see abstract from STN search report].
Also, it is always advisable to couple azide on the spacer, because coupling of azide on the functional peptide, in the case SEQ ID NO:6, may change the property of desired function of the peptide. Moreover, N-terminus is not involved in a folded structure in many proteins. It is therefore likely that N-terminal modification will not affect the inherent function of wild-type proteins or enzymes. Since an N-terminal α-amine has a lower pKa value than the ε-amine of the Lys side chain, reagents can be provided with fine-tuned reactivity to specifically react with the N-terminal amine under appropriate reaction conditions. Therefore, a skilled person in the art would prefer and choose coupling of azide on N-terminal of peptide.
With regard to recited sequences, applicants already acknowledged that these sequences are known in WO2010/000741. Also, for example, Caligiuri teaches fragments of CD31, and one of the sequence is KWPALFVR [see SEQ ID NO:6], which is identical to applicants SEQ ID NO:6. Caligiuri further teaches H-kwpalfvr-OH [see claim 4], which is D-form of applicants SEQ ID NO:6.
With regard to SEQ ID NO:81 is combination of SEQ ID NO:6 and spacer sequence KGGG at N-terminus. Though Caligiuri teaches SEQ ID NO:6 (KWPALFVR), but silent on spacer KGGG. However, KGGG are known in the art, which can be coupled at N-terminus of peptides. For example, Guida teaches KGGG as spacer for short peptides, which allows immobilization of the peptides on the SPR chip surfaces [see Table 1].
For claim 14:
The claimed sequence is nothing but SEQ ID NO:81. As explained above, under For claims 11-13, SEQ ID NO:81 is combination of SEQ ID NO:6 and spacer sequence KGGG at N-terminus, advantages of KGGG. So, the remaining difference is azide group at N-terminus, this difference is also addressed above under For claims 11-13.
Therefore, a skilled person in the art would prefer and choose coupling of azide on N-terminal of peptide.
For claim 15:
Kutryk teaches a reaction between azide and alkyne, which is a click chemistry [see 0156 and Fig.8C].
For claims 16-17:
Though Kutryk silent on the thickness, since methodology is similar and so, the thickness is expected to be in the claimed range, when a skilled person replaces cyclooctyne (DIBAC) and antibody in the teachings of Kutryk with the cyclooctyne of van Delft, and CD31-derived peptide, absent evidence to the contrary.
For claims 18-19:
Kutryk further teaches that their medical device is stent and medical device may comprises metal or an alloy [see 0021-0023].
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, applicants individual components in the claimed method were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed method with a reasonable expectation of success.
Conclusion
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 SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 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, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
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