-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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on October 22, 2025 has been entered.
Priority
This application is a 371 of PCT/EP2020/060932 filed on 04/17/2020, and claims foreign
priority in French application FR 19/04134 filed on 04/17/2019.
Claim Status
Claims 1-5, 7, 9, 10, 13, and 14 are pending and examined. Claims 6, 8, 11, and 12 were
canceled. Claim 1 was amended. Claim 14 was newly added.
Withdrawn Claim Rejections -35 USC§ 112
Indefiniteness rejections over insufficient antecedent basis of the phrase “the at least one crosslinking agent” and the recitation of “such as” in claim 1 are withdrawn because the rejections were obviated with claim amendments.
Withdrawn Claim Rejections - 35 USC§ 103
After further consideration, rejections of claims 1-5, 7, 9-10, and 13 over Guillen et al. (US 2019/0046687 Al, published 14 February 2019) as evidenced by Robertson
(Dynamic Mechanical Properties, published 2014) and Helmenstine (The Arrhenius Equation
Formula and Example, published 16 April 2019) in view of Barg et al. (WO2013185934Al,
published 19 December 2013) are withdrawn because Guillen and evidentiary references are not required to reject the current claims.
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 1-5, 7, 9, 10, 13, and 14 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 was amended to further define the crosslinking agent by providing a list from
which the crosslinking agent is chosen. The claim is indefinite because the end of the claim recites "a bis- or polyepoxide, and a combination thereof”. This is improper Markush language and the list does not make the alternatives clear. To obviate the grounds of rejection it is
recommended to amend the phrase to “a bis-epoxide, a polyepoxide, and a combination thereof”.
Claim 7 recites the limitation "the mixture" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claims 2-5, 9, 10, 13, and 14 are indefinite because the claims depend from an indefinite base claim and contain all indefinite limitations.
Claim Rejections – 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 9, 10, 13, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Barg et al. (WO2013185934 Al, published 19 December 2013).
The claims encompass a formulation obtained according to the process of claim 1.
Barg teaches Example 1, which is a method of making a hydrogel by crosslinking sodium hyaluronate having a molecular weight of from 2.5 MDa to less than 3.0 MDa with BDDE. Dialysis of gels is performed using a buffer solution. The final product is described as an isotonic, sterile, viscoelastic injectable gel (paragraphs 00261-00272). Example 3 teaches performing the method according to Example 1 with the difference that an anesthetic such as lidocaine is added to the gel.
The claims describe the product as a product by process. See MPEP 2113. The specification was reviewed and there is no evidence that the claimed method steps are critical nor that the method of Barg would have produced a product that is materially different than the instantly claimed product. The claimed product is anticipated because its structure is met by the hydrogel of Example 3. The hydrogel of example 3 is a hydrogel comprising hyaluronic acid crosslinked with BDDE, and lidocaine. The hydrogel underwent dialysis in buffer solution and is described as isotonic and injectable gel, which means that that hydrogel is hydrated. The sodium hyaluronate having a range of molecular weights anticipates claim 13 because it is a mixture of hyaluronic acid salts having different molecular weights. The range of molecular weights in claim 14 is anticipated because it encompasses 2.5-3.0 MDa.
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.
Claims 1-3, 5, 7, 9-10, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Barg et al. (WO2013185934 Al, published 19 December 2013).
The claims encompass a process for preparing a formulation comprising at least one crosslinked polymer obtained according to a crosslinking process, comprising at least the following steps:
a) providing a polymer;
b) providing at least one crosslinking agent;
c) carrying out one or more crosslinking step(s) in the presence of said polymer and the at least one crosslinking agent;
d) obtaining the crosslinked polymer; and
(e) at least one step selected from among hydration and swelling:
wherein the crosslinking step or each of the crosslinking steps is carried out at a constant
temperature or at a temperature that varies linearly or in a stepwise manner, the constant or
variable temperature being less than or equal to 9°C, and wherein the one or more crosslinking
step(s) has a duration of between 3 and 72 hours, and
wherein the at least one crosslinking is chosen from the group consisting of the listed
crosslinking agents.
The teachings of Barg are related to a method of preparing a crosslinked polysaccharide (Abstract) intended for use a dermatological filler (paragraph 0017). The teachings include a method of preparing a composition, such as a gel, the composition comprising a crosslinked first
polymer, optionally a second polymer, the second polymer may be crosslinked or non-crosslinked, and water, wherein the first and the second polymer are selected from a polysaccharide, the method comprising at least steps (i) to (iv):
(i) crosslinking a mixture comprising the first polymer and water;
(ii) subsequent to the crosslinking in step (i), terminating the crosslinking;
(iii) optionally blending the product obtained in step (ii) with the second polymer;
(iv) subjecting the product obtained in step (ii) or step (iii) to dialysis (paragraphs 0019 and 0052). In one embodiment, the reaction temperature in step (i) is controlled from 0 to 40 °C (paragraphs 0036, 0070, and 0071). In one embodiment, in step (i), 1 ,4-butanediol diglycidyl ether (BDDE) is used as crosslinking agent (paragraph 0041 and 0068). The ratio between the loss module G" and the storage module G' may be expressed by the loss factor tan5 = G" / G' (paragraph 0055). Such temperatures or temperature ranges may ensure a very homogenous
crosslinking avoiding inhomogeneous particles as far as possible. Furthermore, in one embodiment, the control of the temperature allows the tailor-made adjustment of the viscoelastic properties of the composition according to the invention (paragraph 0076). The varying of the reaction temperature allows for the preparation of compositions such as gels having different viscoelastic properties (paragraph 0077). Step (iv) serves for adjusting the swelling of the gel obtained in step (ii) or step (iii) (paragraphs 00127-00131). In one embodiment, tan5 of the composition obtained in step (iv) ranges from 0.1 to 0.9 measured at a frequency of 0.7 Hz and 30 °C such as from 0.1 to 0.5, or from 0.2 to 0.4 (paragraph 00154). In one embodiment, a local
anesthetic and / or anti-arrhythmic drug may be added to the composition or gel according to the invention obtained in step (iv), if necessary or desired. Such drug may relieve itching, burning and pain, which might arise from skin inflammation when the composition or gel according to the invention is injected into skin tissue (paragraph 00159).
Example 1 teaches a method of making a hydrogel by crosslinking sodium hyaluronate having a molecular weight of from 2.5 MDa to less than 3.0 MDa with BDDE where the crosslinking reaction step (i) occurs for about 3 hours at 30°C. Dialysis of gels is performed using a buffer solution. The final product is described as an isotonic, sterile, viscoelastic injectable gel (paragraphs 00261-00272). Example 3 teaches performing the method according to Example 1 with the difference that an anesthetic such as lidocaine is added to the gel.
Regarding claim 1, 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 modified the method in Example 1 by varying the reaction temperature in the range of 0-40°C, with a reasonable expectation of success because Barg teaches 0-40°C as a suitable temperature range for the crosslinking reaction in step (i). Modified method in Example 1 meets the claimed steps of a) providing a polymer and b) at least one crosslinking agent, c) carrying out a crosslinking reaction to obtain a crosslinked polymer, d) obtaining the polymer, and e) hydrating the crosslinked polymer. The claimed range of between 3 and 72 hours is obvious because it overlaps with the range of approximately 3 hours. The claimed temperature range of less than or equal to 9°C is obvious because it overlaps with 0-40°C. It would have been obvious to have performed the reaction at constant temperature because Barg exemplifies a constant temperature in the crosslinking reaction. It was known from Barg that the control of temperature allows the tailor-made adjustment of the viscoelastic properties of the composition, therefore, one skilled in the art would have been motivated to vary and optimize the reaction conditions to achieve viscoelastic properties that render the hydrogel suitable for use as dermal fillers. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. [W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (See MPEP 2144.05 (Il)(A)).
Regarding claim 2, it would have been obvious to have carried out the crosslinking reaction at a constant temperature because Barg exemplifies crosslinking reactions at a constant temperature.
Regarding claim 3, Tan delta is defined as the ratio of the viscous modulus G” divided by the elastic modulus G’ (paragraph 0035 of the instant application). It would have been obvious to have formed the hydrogel having a tan delta in the range of 0.1 to 0.9 measured at a frequency of 0.7 Hz at 30°C because Barg teaches tan5 (G”/G’) in the range from 0.1 to 0.9 measured at a frequency of 0.7 Hz at 30°C as suitable in hydrogels formed form HA crosslinked with BDDE and intended for use in dermal fillers. The claimed range is obvious because it overlaps with 0.1-0.9. Barg does not teach the same method of measuring as claim 3, however the Office does not have the means to test prior art products for purpose of comparison to instantly claimed products and methods of measuring properties of claimed products.
Regarding claim 5, Barg teaches hyaluronic acid.
Regarding claim 7, it would have been obvious to have formed the hydrogel with a mixture of 2, 3, 4, or 5 different polysaccharides where the polysaccharides are selected from starch, glycogen, cellulose, chitin, and hyaluronic acid, with a reasonable expectation of success because Barg teaches that the composition such as the gel mandatorily requires the use of a polysaccharide as the first, and if a second polymer is used also the use of a polysaccharide as the second polymer (paragraph 0056), where examples of polysaccharides includes starch, glycogen, cellulose, chitin, hyaluronic acid, or mixtures thereof (paragraph 0057).
It would have been obvious to have crosslinked each polymer separately followed by forming a mixture of individually crosslinked polymers which results in the formation of an interpenetrating network, with a reasonable expectation of success because Barg teaches mixing crosslinked polymers. Barg teaches the steps for making a crosslinked polysaccharide formulation by blending a crosslinked first polymer and a crosslinked second polymer (paragraphs 0019 and 00111). The first and the second polymer may be the same or different from each other (paragraph 00112). It would have been reasonable to expect the step of blending and mixing to form an interpenetrating network of crosslinked polymers because it is the same step as performed in claim 7.
Regarding claim 9, the formulation formed by Barg’s modified example 1 as described above renders the claimed formulation obvious.
Regarding claim 10, it would have been obvious to have further modified Barg’s hyaluronic acid-based hydrogel by including lidocaine, with a reasonable expectation of success because Barg teaches in Example 3 repeating the method of Example 1 with an additional step of including lidocaine in the composition.
Regarding claim 13, Barg teaches using sodium hyaluronate having a range of molecular weights from 2.5 to 3.0 MDa, which renders claim 13 obvious because a composition having sodium hyaluronate in a arrange of molecular weights is a mixture of hyaluronic acid salts having different molecular weights.
Regarding claim 14, The claimed range is obvious because it encompasses 2.5-3.0 MDa.
Claimed invention is obvious because combining prior art elements according to known methods to obtain predictable results supports obviousness.
Claims 4 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Barg as applied to claims 1-3, 5, 7, 9-10, 13, and 14 above, and further in view of Guillen (US 2019/0046687 Al, published 14 February 2019).
The teachings of Barg are relied upon as summarized above. Barg does not teach the limitations of claim 4.
The teachings of Guillen are related to dermal fillers based on crosslinked hyaluronic acid (Abstract), and it would have been obvious to have combined the teachings of Guillen with Barg because they are in the same field of endeavor.
Regarding claim 4, it would have been obvious to have formed Barg’s hydrogel having an elastic modulus between 50 and 1500 Pa, with a reasonable expectation of success because Guillen teaches between 50 and 1500 Pa as a suitable range of elastic modulus for hydrogels formed from crosslinked hyaluronic acid where the hydrogels are intended for use as dermal fillers (paragraph 0049). The claimed range of less than or equal to 1000 Pa is obvious because it overlaps with the prior art range. Guillen does not teach the same method of measuring as claim 4, however the Office does not have the means to test prior art products for purpose of comparison to instantly claimed products and methods of measuring properties of claimed products. The selection of a known property based on its suitability for its intended purpose supports obviousness.
Barg’s hydrogel modified with Guillen meets all of the structural limitations of the instantly claimed hydrogel and it would have been reasonable to expect the prior art hydrogel to have the same properties as claimed hydrogel when tested under identical conditions. Therefore, one skilled in the art would have had a reasonable expectation that the hydrogel of Barg as modified by Guillen, when measured on the same equipment and under the same conditions, would result in the same measured properties as claimed. "Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established," and that [ w ]hen the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not. Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. See MPEP 2112.01 (I).
Claim 13 is additionally rejected over the combination of Barg and Guillen. It would have been obvious to have formed the hydrogel of Barg with mixture of hyaluronic acids or hyaluronic acid salts because Guillen teaches that hyaluronic acid based compositions include crosslinked hyaluronic acid, where hyaluronic acid refers to hyaluronic acid and any of its hyaluronate salts including sodium hyaluronate (NaHA), potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, and combinations thereof (paragraph 0031). It would have been obvious to have formed the composition having a combination of high molecular weight and low molecular weight hyaluronic acid because Guillen teaches embodiments of compositions that contain high and low molecular weight hyaluronic acids (paragraph 0039).
One of skill would have had a reasonable expectation of success in forming Barg’s hydrogel using mixtures as taught by Guillen because the purpose of Guillen is to form a hydrogel intended for use as dermal filler. Combining prior art elements according to known methods to obtain predictable results supports obviousness and the selection of a known material suitable for its intended purpose supports obviousness.
Response to Arguments
Applicant’s arguments submitted in the remarks dated October 22, 2025, were fully considered but are not persuasive for the following reasons.
Applicant's argument that the references do not teach claimed reaction conditions is not persuasive because the cited references teach a range of reaction temperatures and a range of crosslinking reaction durations that overlap with the instantly claimed range of temperatures and reaction durations. See MPEP 2144.05.
Applicant’s arguments against Guillen’s zero length crosslinker are not persuasive because Guillen teaches HA crosslinked with BDDE, which renders applicant’s invention obvious. The teaching of a zero length crosslinker does not take away the explicit teaching of HA crosslinked with BDDE. The rejection has been modified to make Barg the primary reference and Guillen is relied upon for limitations of claims 4 and 13.
Applicant’s arguments related to the duration of crosslinking reaction of about 3 hours and varying the temperature in the range of 22-31.33°C in the four examples in Brag are not persuasive because the reference is not limited by examples and it has to be considered in its entirety. Brag teaches 0-40°C as a suitable crosslinking reaction temperature in step (i) where HA is crosslinked with BDDE and a reaction time of about 3 hours, therefore it would have been obvious to have varied the temperature across the entire range and carried the reaction for about 3 hours in order to arrive at a hydrogel having viscoelastic properties suitable for dermal fillers.
Applicant argued that the rection conditions in claim 1 are critical and referred to the declaration under 37 CFR 1.132 by Tranchepain.
Applicant's arguments related to unexpected results and the data provided in the declaration are not sufficient to obviate the grounds of rejection because the applicant has not met the requirements set forth in MPEP 716.02 for at least the following reasons.
Any differences between the claimed invention and the prior art may be expected to
result in some differences in properties. The issue is whether the properties differ to such an
extent that the difference is really unexpected. It is unknown why the applicant considers the
observed G’ and tan delta results unexpected. The reactions were performed under different reaction conditions and it would not have been reasonable to expect gels to have identical G’ and tan delta. In fact, it was known from Barg that varying temperature allows the tailor-made adjustment of the viscoelastic properties of the composition (paragraph 0076 and 0077).
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." The results provided in the declaration do not provide any statistical analysis or data.
The claims are not commensurate in scope with the process that forms compositions that have the asserted unexpected properties. Formulations 2, 4, 5, and 6 were formed from specific precursors (hyaluronic acid of specific molecular formula and BDDE) and reagents in specific amounts, whereas process in claim 1 broadly requires a polymer, and at least one crosslinking agent selected from a list of crosslinking agents without any limit on amounts. The claimed method does not require any other regents. The inventive methods were performed at temperatures 2°C, 5°C, and 9°C, whereas the claims require a range of less than or equal to 9°C. The inventive methods carried out the reactions for 3 hours and 24 hours, whereas the claims require 3-72 hours. The results obtained for the four inventive methods are not sufficient to show that the asserted unexpected results can be extrapolated to the entire breadth of the claims. These results are not sufficient to show that the claimed temperature and reaction time ranges are critical parameters that produce unexpected properties in hydrogels made according to the claimed processes.
Barg teaches a tan5 value (which is equivalent to claimed tan delta) in the range of 0.1-0.9. The skilled artisan would have been motivated vary the reaction conditions in order to arrive at said range. Guillen teaches an elastic modulus in the range of 50-1500 Pa in crosslinked HA intended for use as dermal filler, and the skilled artisan would have been motivated to make the hydrogel having an elastic modulus in the range that is known as suitable, which would have been accomplished by varying the reaction conditions. The comparative examples 1, 3, and 7 have a tan delta that is outside the range the range 0.1-0.9 as taught by Barg. The comparative examples 3 and 7 additionally have a G’ (elastic modulus) that is outside the range of 50-1500 Pa as taught by Guillen. Barg teaches that the crosslinking reaction requires about 3 hours to complete, and the skilled artisan would not have had a reason to perform the reaction for 1 hour, 120 hours, and 24 hours as shown in comparative examples 1, 3, and 7. A person skilled in the art would have run the crosslinking reaction for about 3 hours and varied the temperature from 0°C to 40°C because these are the parameters taught by Barg and it was known from Barg that varying the temperature affects the viscoelastic properties of the final product. The skilled artisan would have varied the conditions in order to arrive at gel having tan delta in the range of 0.1-0.9 and G’ of 50-1500 Pa because these properties were known from Barg and Guillen, respectively, as suitable for hydrogels intended for dermal fillers. The skilled artisan would have arrived at the claimed invention through routine experimentation. The properties that applicant considers desirable in formulations 2, 4, 5, and 6 fall in the ranges taught by Barg and Guillen.
Whether the unexpected results are the result of unexpectedly improved results or a
property not taught by the prior art, the "objective evidence of nonobviousness must be
commensurate in scope with the claims which the evidence is offered to support." In other
words, the showing of unexpected results must be reviewed to see if the results occur over the
entire claimed range. The applicant did not show, with data, that the asserted unexpected
properties would have occurred over the entire breadth of the claims.
To establish unexpected results over a claimed range, applicants should compare a
sufficient number of tests both inside and outside the claimed range to show the criticality of the
claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
An affidavit or declaration under 37 CPR 1.132 must compare the claimed subject matter
with the closest prior art to be effective to rebut a prima facie case of obviousness.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the
examiner should be directed to Alma - Pipic whose telephone number is (571)270-7459. The
examiner can normally be reached M-F 9:00am-5:00pm. 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, Michael Hartley can be reached on 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visithttps://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a US PTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALMA PIPIC/Primary Examiner, Art Unit 1617