*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 .
Applicant's responses dated January 21, 2026 and February 14, 2026 are acknowledged.
Priority
This application is a continuation of 16/341,726 filed on 04/12/2019, which is a 371 of
PCT/IB2017/056342 filed on 10/13/2017, which claims benefit in provisional application
62/407,650 filed on 10/13/2016.
Claims Status
Claims 1-14 are pending. Claims 1-4, 13, and 14 were amended. Claims 2-5 and 7-14 remain withdrawn. Claims 1 and 6 are examined.
It is noted that the claim set filed on February 14, 2026 does not comply with 37 CFR 1.121 because claim 6 is under consideration and the claim was not withdrawn.
New Claim Rejections – 35 USC § 112
Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 does not further limit claim 1 because claim 1 requires the hydrogel to further comprise fibrinogen.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained Claim Rejections - 35 USC§ 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness
rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35
U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the
claims the examiner presumes that the subject matter of the various claims was commonly
owned as of the effective filing date of the claimed invention(s) absent any evidence to the
contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and
effective filing dates of each claim that was not commonly owned as of the effective filing date
of the later invention in order for the examiner to consider the applicability of 35 U.S.C.
102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Altschuler
(WO 2013/171736 Al, published November 21, 2013) and D'Este (Carbohydrate Polymers, 108
(2014) 239-246).
The claims encompass a hydrogel comprising collagen or collagen like peptide, wherein
the collagen or CLP is crosslinked into a network using DMTMM as the crosslinker, and
wherein CLP is not conjugated to PEG.
The teachings of Altschuler are related to biomatrix hydrogels and methods of their use
(Title). In some embodiments, the hydrogel comprises crosslinked collagen, fibrinogen, among
others, and a combination thereof (paragraphs 0032 and 0159). Formulations 5 and 6 describe
hydrogels comprising collagen and fibrinogen (paragraph 00365 and 00367). Combinations with
covalently crosslinked collagen gel are prepared using crosslinking agents such as EDC and
NHS (paragraphs 00366 and 00367).
Altschuler does not teach using DMTMM to crosslink the collagen.
The teachings of D'Este are related to a systemic analysis of DMTMM vs. EDC/NHS for
ligation of amines to hyaluronan in water (Title). The activation of carboxyl groups with
EDC/NHS for amide formation is the standard method for amine ligation to HA, and a very well
established wide-ranging bioconjugation method. The purpose of the analysis is to compare
DMTMM to EDC/NHS activation chemistry for HA ligation using an array of substrates. For all
the substrates tested DMTMM yields were superior a parity of feed ratios. DMTMM chemistry
resulted in effective also in absence of pH control, which is essential for EDC/NHS conjugation.
DMTMM-mediated ligation is a new promising chemical tool to synthesize HA derivatives for
biomedical and pharmaceutical applications (Abstract). Scheme 1 shows the mechanism of
activation of carboxylic acid group on HA followed by coupling to an amine containing
compound R-NH2 where the coupling results in the formation of an amide linkage between the
HA and the R. DMTMM is soluble and stable in water for an extended period of time. This
feature is unique compared to EDC/NHS. DMTMM does not display degradation at room
temperature in water, with 100% recovery after 3 hours. DMTMM does not require pH control,
which is more practical because it reduces the quantity of chemicals to be used and disposed and
simplifies the purification steps. These aspects are a clear advantage for lab and industrial scale
production of HA derivatives (page 242 left column). Conclusion section in paragraph bridging
pages 245-246 summarizes the benefits of using DMTMM relative to EDC/NHS.
The teachings of Altschuler and D'Este are related to methods of conjugating
biopolymers via carboxylic acid group activation with EDC/NHS, and it would have been
obvious to have combined them because they are in the same field of endeavor. It would have
been prima facie obvious to a person of ordinary skill in the art before the effective filing date of
the claimed invention to have formed a hydrogel comprising fibrinogen and crosslinked
collagen, with a reasonable expectation of success because Altschuler teaches a hydrogel
comprising fibrinogen and crosslinked collagen. It would have been obvious to have crosslinked
the collagen using EDC/NHS because Altschuler teaches that the crosslinked collagen is
obtained by reacting collagen in the presence of EDC/NHS. It would have been obvious to have
modified Alschuler' s collagen crosslinking method by replacing EDC/NHS with DMTMM, with
a reasonable expectation of success because D'Este teaches that DMTMM is useful for conjugating biopolymers such as hyaluronic acid by activating the carboxylic acid group where
the activated carboxylic acid group subsequently reacts with an amine containing compound to
create an amide linkage thereby conjugating the amine compound to the hyaluronic acid. The
skilled artisan would have understood that collagen crosslinking with EDC/NHS occurs by
activation of carboxylic acid groups followed by reaction of activated carboxylic acid groups
with amine groups on the collagen thereby forming a crosslinked collagen via amide linkages.
One of skill in the art would have been motived to replace EDC/NHS with DMTMM because D’Este teaches that DMTMM is superior to EDC/NHS and the main benefits include no need of pH shifting during the reaction, improved yields at equivalent stochiometric ratios, reduced quantity of coupling agent necessary, and no need for buffering the reaction mixture. Combining prior art references to yield predictable results supports obviousness. 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.
Response to Arguments
Applicant’s arguments and the declaration submitted in the remarks dated January 21, 2026 and February 14, 2026 were fully considered but are not persuasive for the following reasons.
It is apparent from D’Este’s Scheme 1 that the purpose is to activate the carboxyl group in HA by reacting with DMTMM and conjugate the activated carboxyl group with an amine containing compound. Scheme 1 shows several examples of conjugating HA to anther compound using DMTMM where the final product is HA linked to the compound via an amide linkage. D’Este teaches using DMTMM to directly conjugate HA to another compound where the conjugation occurs by forming a amide linkage between the native carboxyl group in HA and the native amine group on the other compound. The examiner disagrees with applicant’s characterization of D’Este’s Scheme 1 where applicant argued that ADH, AADA, GlyOEt, NED, BSA, Dox, and pNIPAM are crosslinkers. The description of Scheme 1 states that the top of the scheme describes amidation of HA and the bottom describes moieties grafted to HA. Moieties depicted on the bottom are ADH, AADA, GlyOEt, NED, BSA, Dox, and pNIPAM, which are not crosslinkers nor does D’Este ever describe these moieties as crosslinkers. It is apparent from Scheme 1 that amine-containing moieties depicted on the bottom are grafted or conjugated to HA using DMTMM by activating native carboxyl groups on HA and reacting with the amine group thereby forming HA conjugated to the various moieties via direct linkage through an amide formed between the carboxyl and the amine group.
D’Este’s method of conjugating HA to the various amine-containing compounds is irrelevant in the instant case because the claimed invention is drawn to a product and not a method of making a product. D’Este’s teaching of removing unreacted DMTMM from HA-HMTMM prior to introducing the amine-containing compound does not affect the rejection of claims. It is clear from D’Este’s teachings that the amine-containing compounds in Scheme 1 are grafted onto HA and they are not crosslinkers.
Applicant’s argument that D’Este would not be applicable to direct crosslinking of collagen of collagen-like peptide via lysine amino groups is not persuasive applicant did not present evidence that amine groups on the collagen would not react with DMTMM activated carboxyl groups on collagen. D’Este teaches conjugating HA-DMTMM to molecules as small as GlyOEt and molecules as large as bovine serum albumin and pNIPAM.
Applicant’s argument that all claimed embodiments proceed via direct amide bond formation between carboxyl groups and amino group, whereas D’Etse final products have bridge crosslinks; is not persuasive because it is apparent from Scheme 1 that conjugation of the amine-containing compound and the activated HA occurs directly between the carboxyl and the amine group. Additionally, direct crosslinking of collagen with itself was taught by Altschuler, where EDC/NHS was used to activate the carboxyl groups and activated carboxyl groups react with native amine groups on the collagen. Replacing EDC/NHS with DMTMM in Alschuler would have been obvious because D’Etse showed that DMTMM was known to activate carboxyl groups on HA and that activated carboxyl group reacts with native amine groups on various compounds including a protein and a polymer. Furthermore, direct amide bond formation between collagen carboxyl and collagen amino group is not a claimed limitation.
Applicant’s argument that there would not have been a reasonable expectation of success in crosslinking collagen with DMTMM because amino group on the lysine residue of collagen has different chemistry compared to the different amino groups on compounds exemplified by D’Este and that the amino group on the lysine residue would be far less nucleophilic under comparable conditions, is not persuasive because applicant did not present any actual evidence support the argument that amino groups on the lysine residue of collagen would not react with DMTMM activated carboxyl group on the collagen. The purpose of Altschuler is to form crosslinked collagen where crosslinks are between EDC/NHS-activated native carboxyl groups and native amino groups. DMTMM was a known alternative to EDC/NHS for successfully forming amide linkages during conjugation of biomolecules. The skilled artisan would have been capable of determining reaction conditions under which the native amine group would successfully react with the native activated carboxylic acid groups in order to crosslink collagen by reacting said groups to form amide linkages. The reasonable expectation of success is present in the teachings of the cited references.
Applicant’s argument related to the differences between reaction conditions in D’Este and applicant’s specification are not sufficient to overcome the rejection because the claims are drawn to a product and not to a method of making the product. As stated above, the skilled artisan would have been capable of modifying the conditions in Altschuler in order to replace EDC/NHS activator with DMTMM activator in order to arrive at crosslinked collagen where the crosslinks are between native carboxyl groups and native amine groups. The skill artisan would have been aware that the conditions would have to be tailored to collagen chemistry because the purpose is to crosslink collagen.
Applicant’s arguments related to the effect of PEG on crosslinking are not sufficient to overcome the rejection because the effects of PEG on crosslinking are not relevant to the current rejection. The claims expressly exclude the presence of PEG and none of the cited references require PEG. It is reiterated that the claimed embodiments are not limited to a process that proceeds via direct amide bond formation between the carboxyl groups present or collagen or CLP backbones and e-amine groups of lysine residues.
Arguments directed to the purpose of DMTMM in D’Este are not sufficient to overcome the rejection because the skilled artisan would have understood that the reaction mechanism by which DMTMM activates a carboxylic acid group and the activated carboxylic acid group reacts with an amine group to form an amide linkage can be applied to crosslinking collagen where the native carboxylic acid groups react with native amine groups to crosslink the collagen by forming amide linkages. Forming crosslinked collagen via amide linkages formed by reacting activated native carboxylic acid groups with native amine groups was known from Altschuler where EDC/NHS was used to activate the carboxylic acid groups, and replacing EDC/NHS with DMTMM with a reasonable expectation of success would have been obvious in view of the teachings of D’Este. The rejection is a proper obviousness rejection because the combination of references teaches motivation to combine and modify and the combination teaches all of the claimed limitations and motivation to arrive at the claimed limitations. A proper obviousness rejection does not require a single reference that teaches all of the claimed limitations. "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle."Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ."Id. at 418, 82 USPQ2d at 1396.
Argument that prior art teaches away from using DMTMM as a crosslinker because D’Este teaches removing unreacted DMTMM is not persuasive because DMTMM was used to activate carboxylic acid groups and only the unreacted DMTMM was removed prior to grafting the HA with an amine-containing compound. DMTMM was a known carboxylic acid group activator and it would have been obvious to use it as such in the crosslinking of collagen as taught by Altschuler.
Arguments directed to undue experimentation are not sufficient to obviate the grounds of rejection because it is within the skill of a person of ordinary skill in the art to determine reaction conditions necessary to accomplish crosslinking collagen by activating its native carboxylic acid groups with DMTMM.
Applicant’s request for reconsideration of the restriction requirement was considered however it is not persuasive and the restriction requirement is maintained for reasons of record.
The declaration was fully considered however it is not found sufficient to obviate the grounds of rejection for reasons described above. Applicant’s arguments presented in the remarks are based on the statements made in the declaration.
Conclusion
No claims are 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.
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/ALMA PIPIC/Primary Examiner, Art Unit 1617
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