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 . 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.
Priority
The instant application is a 371 of PCT/US2022/046831 filed on 10/17/2022 and claims domestic benefit to US provisional application no. 63/355,884 filed on 06/27/2022 and US provisional application no. 63/256,108 filed on 10/15/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/12/2024 and 11/10/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Claims
The preliminary claim amendments filed on 04/12/2024 is acknowledged. Claims 1, 3, 5, 7-8, 10, 12, 18, and 23 are amended. Claims 2, 4, 6, 9, 11, 13-17, and 19-22 are cancelled. Claims 24-32 are newly added.
Accordingly, claims 1, 3, 5, 7-8, 10, 12, 18, and 23-32 are pending and being examined on the merits herein.
Claim Objections
Claims 26 and 31 are objected to because of the following informalities:
The Formula (I) in claim 26 has poor resolution of the chemical structure and poor legibility of the subscripts.
Claim 31 is missing the required period at the end of the claim sentence. See MPEP 608.01(m).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 23, 26, and 28-29 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 23 recites “A use of”, which is suggestive of a method. However, an attempt to claim a process without setting forth any steps involved in the process raises an issue of indefiniteness. See MPEP 2173.05(q).
Claim 26 recites a modified or crosslinked hyaluronic acid represented by Formula (I). The structure recites a R group and a x variable. However, the R group and x variable are undefined in the claim, making it unclear what the metes and bounds are for the claim.
Claim 29 depends from claim 26 but does not overcome the described indefinite issue.
For purposes of examination, the recited R group is being interpreted as any chemical group, and the x variable is being interpreted as being any value between 0.0001 to 0.05 to be consistent with the recited chemical modification or crosslinking percentage of 0.01 to 5.0 percent.
Claim 28 recites “R is (-CH2-CH2-S-R’). The R’ group is undefined in the claim, making it unclear what the metes and bounds are for the claim.
For purposes of examination, the recited R’ group is being interpreted as any chemical group.
Claim Rejections - 35 USC § 112(d)
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 29 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 29 recites “The chemically modified or crosslinked hyaluronic acid of claim 26 further comprising variations of Formula (I), wherein other groups on hyaluronic acid are chemically modified or crosslinked”.
Claim 29 fails to further limit the chemically modified or crosslinked hyaluronic acid of claim 26 because claim 29 recites new, additional modifications to the claim 26 hyaluronic acid structure, which broadens the scope of claim 29.
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.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 26-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 26 recites a chemically modified or crosslinked hyaluronic acid represented by the recited Formula (I).
Even though the instant specification references a crosslinked hyaluronic acid such as in paragraph 0009 and 0010 (page 3), the simple recitation of a crosslinked hyaluronic acid does not provide enough disclosure for the exact chemical modifications on the hyaluronic acid backbone for the crosslinking as seen in the recited Formula (I) structure, and the instant specification does not disclose the recited Formula (I) structure. Therefore, the claim contains subject matter that was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s) had possession of the claimed invention.
For purposes of compact prosecution, the rejections below are being applied on the basis that Applicant has support for the recited Formula (I) structure.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 23 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because it is unclear if the claim is directed toward a product (crosslinked precipitate of claim 1) or a method (treating inflammation, osteoarthritis, ocular disease, cardiovascular disease, disc degeneration, diabetic ulcers, and pain, reducing inflammation following, or improving tissue healing following surgery or a traumatic injury). See MPEP 2173.05(q).
For purposes of examination, claim 23 is being interpreted as being directed toward a product (crosslinked precipitate of claim 1) and the additional recited uses are being interpreted as intended uses of the product.
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.
Claim(s) 1, 3, 5, 7-8, 12, 18, 23, and 30-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US20230021037A1 in PTO-892, effective filing date of 11/18/2019) in view of Sahoo et al. (Biomacromolecules, 2008 in PTO-892) and Kim et al. (US20220040374A1 in PTO-892, effective filing date of 12/07/2018).
Wang discloses a preparation method of a hydrogel of a mercapto-modified macromolecular compound includes the steps of combining the mercapto-modified macromolecular compound with an acrylated macromolecular compound and/or an acrylated micromolecular crosslinker (Abstract).
Wang discloses that hyaluronic acid (HA) is a widely used naturally occurring polymer for various medical applications such as orthopedics, gynecology, plastic surgery, drug delivery systems, tissue repair, etc. (paragraph 0004 and claim 10). However, Wang discloses that HA has poor stability and a short half-life (paragraph 0005), and while several modifications have been made to the HA to overcome these limitations, there is still need to further control and tune the modifications for medical applications (paragraph 0006-0007). Therefore, Wang presents their novel hydrogel to solve the described limitations and make it suitable for use across a wide filed of applications including biopharmaceuticals, medical cosmetology, cosmetics and the like (paragraph 0008).
Wang demonstrates in Example 1 a preparation of crosslinked hyaluronic acid hydrogel (paragraph 0319-0323). 10 mg of acryloylated hyaluronic acid polymer such as HA-A2 was dissolved in 1 mL of phosphate buffer (1% (w/v) concentration) and 10 mg sulfhydryl-modified hyaluronic acid polymer such as HA-A2-SH1 was dissolved in 1 mL of phosphate buffer (1% (w/v) concentration) (paragraph 0319-320). The two polymers were then mixed in equal volume and physiological in suite cross-linking reaction between the two polymers occurred immediately (paragraph 0321).
Wang provides several examples of preparing the two modified polymers that can be mixed together to form the crosslinked HA described above.
Wang provides several examples for the synthesis of the acryloylated hyaluronic acid polymer such as Preparation Example 2 HA-A2 (paragraphs 0197-0199) and Preparation Example 4 HA-MA2 (paragraphs 0203-0205). 1 gram of hyaluronic acid was dissolved and mixed with either 6.3 grams of acrylic anhydride or 7.7 grams of methacrylic anhydride at a pH of 8. A large amount of precipitate was generated and further purified to obtain a lyophilized white flocculent solid. Wang also discloses in Preparation Example 1 HA-A1 (paragraphs 0194-0196) and Preparation Example 3 HA-MA1 (paragraphs 0200-0202) a method of making the acrylolylated HA polymer by mixing with glycidyl acrylate or glycidyl methacrylate.
The HA-A2 structure is shown in FIG. 16 and below:
PNG
media_image1.png
323
601
media_image1.png
Greyscale
The HA-A2 structure shown is the same structure as the Formula (I) structure shown in instant claim 26 when R is -CH=CH2 as recited in instant claim 27.
Wang provides several examples for the synthesis of the sulfhydryl-modified hyaluronic acid polymer such Preparation Example 6 (paragraphs 209-211). 1 gram of the HA-A2 prepared in Preparation Example 2 was further mixed with 0.3 gram of dithiothreitol (VWR). The resulting mixture was purified and lyophilized to obtain HA-A2-SH1 as a while flocculent solid. The HA-A2-SH1 structure is shown in FIG. 2 and shown below:
PNG
media_image2.png
399
644
media_image2.png
Greyscale
The right unit (SH1) contains the same R group recited in instant claim 28.
Wang demonstrate that the Example 1 hydrogel had the following crosslinking structure:
PNG
media_image3.png
276
681
media_image3.png
Greyscale
The * represents the linking site of either of the two modified HA polymers.
Wang discloses that the hydrogel may be further added with at least one of other biological functional materials (such as hyaluronic acid, collagen, gelatin, chondroitin sulfate, chitosan and sodium alginate), drugs, growth factors, cell suspensions, and the like (paragraph 0179). Wang discloses that the introduction of collagen or gelatin can make the hydrogel system more similar to the composition of soft tissues of an organism (paragraph 0179)
Wang further demonstrates in Example 7 (paragraphs 0337-0340) an animal experiment for the shaping effect of the hydrogel. 10 mg/mL concentration of each the HA-A2 and HA-A2-SH1 aqueous solution were mixed together and injected via syringe into the subcutaneous part of the back of a mouse. After 60 minutes form injection, the hydrogel formed subcutaneously in the mouse and was maintained 12 weeks after injection (paragraph 0338). The hydrogel had a good morphology and the local state of the surrounding tissue had no abnormalities such as inflammation, infection, and necrosis. The results show the hydrogel had degradation resistance and maintenance of gel stability.
While Wang demonstrates a crosslinked hyaluronic acid hydrogel comprising two different fractions of hyaluronic acid, Wang does not disclose that the crosslinks are hydrolytically degradable and does not disclose that the hydrogel is precipitated.
Sahoo discloses hydrolytically degradable hyaluronic acid (HA) hydrogels with controlled temporal structures (Abstract).
Sahoo discloses that HA can be readily modified through its carboxyl and hydroxyl groups to form hydrogels in the presence of water and have found numerous applications in tissue regeneration, drug delivery, and microdevices (second paragraph left column page 1088). However, Sahoo discloses that the design of these current hydrogels is limiting in that (i) enzymes are needed to degrade the hydrogel, which can hinder the diffusion of growth factors, migration of cells, and distribution of extracellular matrix proteins if enzymes are not abundant and (ii) degradation products are typically modified forms of HA (e.g., due to methacrylate addition) rather than potentially biologically active unmodified HA (second paragraph left column page 1088).
Therefore, Sahoo discloses that in order to overcome these limitations, their work sought to design a new macromer that forms hydrogels that are hydrolytically degradable to allow further control over their structures toward a range of biological applications, and further discloses that these macromers can be polymerized into hydrogels alone or co-polymerized with other macromers to produce hydrogels with diverse properties, specifically related to temporal structures with degradation (last paragraph left column through first paragraph right column page 1088).
Sahoo demonstrates the synthesis of their HA hydrogel in Scheme 1 (page 1089) with the final product (MeLAHA) shown below:
PNG
media_image4.png
374
476
media_image4.png
Greyscale
Sahoo shows that their synthesis involved the inclusion of hydrolytically degradable repeat units of alpha-hydroxy esters (lactic acid) between the HA and the polymerizing moiety (methacrylate). The methacrylate (HEMA) was first modified with the lactide via ring opening polymerization to obtain MeLA-OH, which the end OH group undergoing further modification to couple to the HA to obtain the MeLAHA macromer.
Sahoo further demonstrates that the hydrogel was formed by dissolving MeLAHA macromer and/or MeHA (methacrylate HA) at various concentration ratios in PBS buffer and using a photoinitiator (Igracure 2959) under UV light to polymerize and form the gel (Section “Hydrogel Formation” left column page 1089).
Sahoo discloses that various parameters of the hydrogel including the molecular weight of the HA, the type (e.g., lactic acid versus caproic acid) and number (n) of hydrolytically degradable groups, the extent of coupling (percent of HA repeat units modified) of the degradable groups to the HA backbone, and the concentration of macromer are all readily controllable (second paragraph right column page 1090).
Sahoo demonstrates in Figure 3 (page 1091) that the copolymer concentration ratio (MeLAHA:MeHA) influences the cellular organization and tissue distribution of mesenchymal stem cells (MSCs) encapsulated in the hydrogels (Abstract). Sahoo further demonstrates in Figure 2 (page 1091) that the distribution of released extracellular matrix molecules (e.g., chondroitin sulfate) was improved with increasing amounts of the hydrolytically degradable component (MeLAHA concentration), and further discloses that this macromer allows for enhanced control over the structural evolution of the HA hydrogels toward applications as biomaterials (Abstract).
Kim discloses a crosslinked hyaluronic acid (HA) in the form of a powder and methods of preparing thereof (Abstract).
Kim discloses that existing crosslinked HA products are difficult to filter and thus a lot of effort is required to remove foreign substances contained in the gel, and a large amount of washing buffer is required to wash the crosslinking agent (paragraph 0004). Kim further discloses that the existing crosslinked hyaluronic acid products have a lot of problems in quality uniformity due to severe variations in rheological properties of hyaluronic acid, such as viscoelasticity, etc., according to each production batch. Therefore, quality control is not easy, and a complex process and a lot of cost are required for mass production (paragraph 0004).
Kim presents a method of preparing crosslinked hyaluronic acid product in the form of powder, which is economical and optimized for mass production and exhibits excellent rheological properties and quality uniformity (paragraphs 0007-0010).
Kim discloses that the method involves first crosslinking an aqueous solution of hyaluronic acid using a crosslinking agent, adding ethanol to the solution to solidify the hyaluronic acid into particles, and maintaining the crosslinking reaction of the aqueous solution comprising the hyaluronic acid particles to prepare a crosslinked hyaluronic acid product in the form of powder (claim 19).
Kim discloses that the method further involves hydrating and filtering the powdered crosslinked HA product to obtain a hydrogel (claim 19). Kim discloses that the crosslinked HA hydrogel obtained after filtering exhibits a particle size distribution D90 of 120 μm or less, D10 of 10 μm to 30 D50 of 35 μm to 65 and D90 of 80 μm to 120 μm (claims 20-21).
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted either the HA-A2 or HA-A2-SH1 polymer disclosed in Wang with the MeLAHA polymer disclosed in Sahoo to form the hydrogel and further prepare this modified hydrogel by solidifying into a powder using the method disclosed in Kim to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (HA-A2 or HA-A2-SH1) for another (MeLAHA) to obtain predictable results and would have a reasonable expectation of success in doing so because both Kim and Sahoo demonstrate the formation of crosslinked hydrogels by utilizing two modified HAs, one of which is the same acrylated HA type. Furthermore, both Kim and Sahoo disclose that their respective HA hydrogels are useful for the same medical applications as a biomaterial.
Alternatively, it would have been prima facie obvious before the effective filing date of the claimed invention to have further included the MeLAHA polymer disclosed in Sahoo with the HA-A2 / HA-A2-SH1 disclosed in Wang to form the hydrogel and further prepare this modified hydrogel by solidifying into a powder using the method disclosed in Kim to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to further include the MeLAHA polymer because Sahoo discloses that the inclusion of hydrolytically degradable crosslinked HA, such as their MeLAHA, improved distribution of released extracellular matrix molecules and allows for enhanced control over the structural evolution of the HA hydrogels toward applications as biomaterials.
One of ordinary skill in the art would have a reasonable expectation of success because both Wang and Sahoo demonstrate the formation of a HA hydrogel by crosslinking acrylated HAs. Furthermore, Sahoo discloses that their MeLAHA can be co-polymerized with other macromers to produce hydrogels, and further shows that their MeLAHA macromer has a vinyl end, which is the same end group that is used to crosslink the HA in the methods of Wang.
One of ordinary skill in the art would have been motivated to solidify the hydrogel into a powder because Kim discloses existing crosslinked HA products are difficult to filter and thus a lot of effort is required to remove foreign substances contained in the gel, and that their method of solidifying the crosslinked HA into a powder is economical and optimized for mass production and exhibits excellent rheological properties and quality uniformity.
One of ordinary skill in the art would have a reasonable expectation of success because the method of Kim to solidify the crosslinked HA first involves preparing aqueous HA and performing a crosslinking step on the aqueous HA, which are the same initial preparation steps disclosed in Wang and Sahoo.
Furthermore, solidifying the hydrogel into a powder as disclosed by the combined teachings of Wang, Sahoo, and Kim described above meets the limitation of a crosslinked hyaluronic acid precipitate recited in the instant claims because the solidifying step in the combined references involves adding an ethanol solvent to the crosslinked HA hydrogel to form the powder, which is the same process step used to precipitate the instant crosslinked HA as seen in all of the Examples of the instant specification such as in Example 4, paragraph 00130 (page 27).
In regards to instant claim 18, it would have also been prima facie obvious before the effective filing date of the claimed invention to have further injected the modified HA hydrogel as disclosed by the combined teachings of Wang, Sahoo, and Kim described above for treatment as disclosed in Wang to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Wang demonstrates that the acrylate-thiol hydrogel can be injected into a mouse and maintain morphology with no abnormalities to the surrounding tissue had, and Wang further discloses that their hydrogel can be used for a variety of medical applications such as a drug delivery system or tissue repair scaffold.
In regards to instant claim 23, the modified HA hydrogel as disclosed by the combined teachings of Wang, Sahoo, and Kim described above would be capable of performing the recited intended uses and therefore meets the limitations of instant claim 23. See MPEP 2111.02 II.
In regards to instant claim 31, it would have also been prima facie obvious before the effective filing date of the claimed invention to have included collagen as disclosed in Wang with the modified HA hydrogel as disclosed by the combined teachings of Wang, Sahoo, and Kim described above to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to include collagen with the hydrogel because Wang discloses that the introduction of collagen or gelatin can make the hydrogel system more similar to the composition of soft tissues of an organism
One of ordinary skill in the art would have a reasonable expectation of success because Wang discloses adding additional biological functional materials such as collagen with an acrylate/thiol based HA hydrogel.
In regards to instant claim 32, even though the combined teachings of Wang, Sahoo, and Kim described above do not teach solubilizing in less than 180 days when reconstituted in aqueous buffer at 10 mg/mL and incubated under physiological conditions, this result would flow naturally from the suggestions of the prior art combination because the combined references provide guidance of making the same acrylate/thiol based HA hydrogels, as demonstrated in Examples 4-7 (pages 26-29) of the instant specification, and the combined references provide further guidance that the HA hydrogel can be precipitated into a powder, re-dissolved into a solution to form the hydrogel, and injected into an animal (physiological condition) at the recited 10 mg/mL concentration.
MPEP 2145 II states that “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Wang (US20230021037A1 in PTO-892, effective filing date of 11/18/2019) in view of Sahoo et al. (Biomacromolecules, 2008 in PTO-892) and Kim et al. (US20220040374A1 in PTO-892, effective filing date of 12/07/2018), as applied to claim 1 above, and further in view of Ariyati et al. (J Stem Cells Regen Med, 2019 in PTO-892).
The combined teachings of Wang, Sahoo, and Kim are as described above and teach the crosslinked HA precipitate of instant claim 1 as discussed above. Furthermore, Wang discloses that the degree of the cross-linking reaction of the hydrogel is controllable (paragraph 0009).
The combined references, however, do not teach an extent of crosslinking of 0.01% to 5%.
Ariyati discloses the best degree of hyaluronic acid crosslinking for increasing growth factors level of platelet rich fibrin lysate (Abstract).
Ariyati discloses that HA is frequently utilized as fillers of aging skin tissue through injection (first paragraph left column page P3). However, Ariyati discloses that while HA is able to restore volume and elevate the amount of collagen in the dermis through fibroblast stimulation, this effect is mere temporary in collagen and elastin volume replacement that continues to disappear and fail to make it revert (first paragraph left column page P3). Ariyati further discloses that HA preparation needs to be modified via crosslinking as unmodified HA possesses no durability properties when injected (second paragraph left column page P3).
Ariyati discloses that crosslinking HA will persist longer, around 6-12 months, however the optimal degree of crosslinking has not been identified with some reports showing that very high crosslinking degrees may affect filler biocompatibility and lead to rejection or encapsulation (second paragraph left column page P3).
Therefore, Ariyati aimed to determine the effect of HA mixture with various degrees of crosslinking on GF levels in PRF-L. As seen in Table 1 (page P4) and Figure 1 (page P5), a 3% degree of HA crosslinking triggered the greater release of growth factors (GF) by platelet-rich fibrin lysate (PRF-L) compared to higher HA crosslinking degree (4% and 10%).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HA hydrogel as disclosed by the combined teachings of Wang, Sahoo, and Kim described above to have a degree of crosslinking of 3% as disclosed in Ariyati to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to modify to 3% HA crosslinking because Aryati demonstrates that % degree of HA crosslinking triggered the greater release of growth factors (GF) by platelet-rich fibrin lysate (PRF-L) compared to higher HA crosslinking degree (4% and 10%), which can help further improve chronic fibroblast ulcers and premature aging.
One of ordinary skill in the art would have a reasonable expectation of success because the combined teachings of Wang, Sahoo, and Kim described above teach that the HA hydrogel can be used for cosmetic and tissue repair purposes and further teach that the degree of crosslinking within the HA hydrogel can be controlled.
Additionally, an ordinary skilled artisan would have performed routine optimization to adjust the degree of crosslinking percentage to arrive at the claimed invention, based on Ariyati disclosing that a 3% degree of HA crosslinking triggered the greater release of growth factors (GF) by platelet-rich fibrin lysate (PRF-L) compared to higher HA crosslinking degree (4% and 10%), and Wang teaching that the degree of crosslinking for the HA hydrogel can be controlled. See MPEP 2144.05
Claim(s) 24 is rejected under 35 U.S.C. 103 as being unpatentable over Wang (US20230021037A1 in PTO-892, effective filing date of 11/18/2019) in view of Fenn et al. (J Biomed Mater Res B Appl Biomater. 2016 in PTO-892).
The teachings of Wang are as described above.
Wang discloses that the degree of the cross-linking reaction of the hydrogel is controllable (paragraph 0009).
Wang provides several examples for the synthesis of the acryloylated hyaluronic acid polymer such as Preparation Example 2 HA-A2 (paragraphs 0197-0199) and Preparation Example 4 HA-MA2 (paragraphs 0203-0205). 1 gram of hyaluronic acid was dissolved and mixed with either 6.3 grams of acrylic anhydride or 7.7 grams of methacrylic anhydride at a pH of 8. A large amount of precipitate was generated and further purified to obtain a lyophilized white flocculent solid.
While Wang demonstrates a method of making an acrylate or methacrylate modified hyaluronic acid comprising adding the anhydride to an aqueous solution of HA and maintaining the pH at 8, Wang does not teach the molar ratio of 0.002 to 1.5 acrylic anhydride to hyaluronic acid monomer.
Fenn discloses a visible light crosslinking of methacrylated hyaluronan (MA-HA) hydrogels for injectable tissue repair (Abstract).
Fenn discloses that anhydrous methacrylation (MA) of HA was performed to control the degree of modification (DOM) of HA (Abstract). Fenn discloses that the synthesis of the methacrylated HA involved dissolving the HA in a solvent solution and further mixing with methacrylic anhydride in the presence of a catalyst (first paragraph page 3). Fenn discloses that the amount of MA was adjusted to achieve varying DOMs based on molar ratios of the hydroxyl groups (modification sites) per HA repeat unit to MA, and that the amounts of MA utilized in this study were 1×, 1.5×, and 2× the molar quantity of hydroxyl groups (first paragraph page 3).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HA-A2 preparation method disclosed in Wang by using 1x or 1.5x molar ratios of acrylic anhydride to hydroxyl groups (modification sites) per HA repeat unit as disclosed in Fenn to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both Wang and Fenn disclose the same steps of modifying HA using methacrylate anhydrides to form methacrylated HA hydrogels, and both Wang and Fenn also disclose the use of their HA hydrogels for the same medical application (tissue repair). Furthermore, Wang shows that the methacrylation and acrylation of the HA involve the same steps of mixing the aqueous HA with the anhydride form.
Claim(s) 25-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US20230021037A1 in PTO-892, effective filing date of 11/18/2019) in view of Spearman et al. (J Biomed Mater Res A, 2020 in PTO-892).
The teachings of Wang are as described above.
Wang discloses that the degree of the cross-linking reaction of the hydrogel is controllable (paragraph 0009).
Wang provides several examples for the synthesis of the acryloylated hyaluronic acid polymer such as Preparation Example 2 HA-A2 (paragraphs 0197-0199) and Preparation Example 4 HA-MA2 (paragraphs 0203-0205). 1 gram of hyaluronic acid was dissolved and mixed with either 6.3 grams of acrylic anhydride or 7.7 grams of methacrylic anhydride at a pH of 8. A large amount of precipitate was generated and further purified to obtain a lyophilized white flocculent solid. Wang also discloses in Preparation Example 1 HA-A1 (paragraphs 0194-0196) and Preparation Example 3 HA-MA1 (paragraphs 0200-0202) a method of making the acrylolylated HA polymer by mixing with glycidyl acrylate or glycidyl methacrylate.
The HA-A2 structure of Wang is shown below:
PNG
media_image1.png
323
601
media_image1.png
Greyscale
The HA-A2 structure shown above is the same structure as the Formula (I) structure shown in instant claim 26 when R is -CH=CH2 as recited in instant claim 27.
Wang provides several examples for the synthesis of the sulfhydryl-modified hyaluronic acid polymer such Preparation Example 6 (paragraphs 209-211). 1 gram of the HA-A2 prepared in Preparation Example 2 was further mixed with 0.3 gram of dithiothreitol (VWR). The resulting mixture was purified and lyophilized to obtain HA-A2-SH1 as a while flocculent solid. The HA-A2-SH1 structure is shown in FIG. 2 and shown below:
PNG
media_image2.png
399
644
media_image2.png
Greyscale
The right unit (SH1) contains the same R group recited in instant claim 28. Wang discloses that (n2+n3)/(n1+n2+n3) represents a degree of acryloylation, and n3/(n1+n2+n3) represents a degree of sulfhydrylation (paragraph 0097). Furthermore, Wang discloses that n2 can be 0, and if it is 0, n3/(n1+n3) represents both the degree of acryloylation and the degree of sulfhydrylation (paragraph 0097).
While Wang demonstrates a method of making an acrylate modified hyaluronic acid, Wang does not teach the extent of acrylate chemical modification is 0.01 to 5 percent.
Spearman discloses tunable methacrylated hyaluronic acid (HA) hydrogels as scaffolds for soft tissue engineering applications (Abstract).
Spearman discloses that crosslinked forms of HA are more robust and provide tunable mechanical properties and degradation rates that are critical in regenerative medicine; however, crosslinking modalities reported in the literature vary and there are few comparisons of different scaffold properties for various crosslinking approaches (Abstract). Therefore, Spearman discloses a direct comparison of two methacrylation techniques for HA (glycidyl methacrylate HA (GMHA) or methacrylic anhydride HA (MAHA).
As seen in Table 1 (page 27), the degree of methacrylation ranged from 2.4 to 86% and can be adjusted by tuning the ratio of methacrylate group to HA monomer during synthesis. Wang further demonstrates in Figure 5 (page 23) that the modulus of these different hydrogels ranged from 0.35 kPA to 6.13 kPa, matching the mechanical properties for nine different tissues isolated from rat (ranging from lung at the softest to muscle at the stiffest) (Abstract). Wang further discloses that their hydrogels can support 3D axonal elongation from dorsal root ganglia cultures, and that their methacrylated HA provides a tunable platform with a wide range of properties for use in soft tissue engineering (Abstract).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HA hydrogel preparation method disclosed in Wang by adjusting the stoichiometric ratio of the acrylic anhydride to HA monomer to have a degree of acrylation from 2.4% to 86% as disclosed in Spearman to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Spearman discloses the tuning of mechanical properties of the methacrylated HA by adjusting the stochiometric ratios of the glycidyl/anhydride methacrylate to HA monomer, and an ordinary skilled artisan would have applied the same tuning method for the glycidyl/anhydride acrylate as Wang shows that the methacrylation and acrylation of the HA involve the same steps of mixing the aqueous HA with either the glycidyl or anhydride form. Furthermore, both Wang and Spearman disclose the same steps of modifying HA using glycidyl / anhydride methacrylates to form methacrylated HA hydrogels, and both Wang and Spearman also disclose the use of their HA hydrogels for the same medical application (tissue engineering). Lastly, Spearman discloses that the tuning results in an overlapping degree of methacrylation of 2.4% to 86%, rendering the recited 0.01 to 5.0% degree of modification obvious. See MPEP 2144.05 I.
In regards to instant claim 28, it would have also been prima facie obvious before the effective filing date of the claimed invention modified the HA-A2-SH1 fraction in the HA hydrogel as disclosed by the combined teachings of Wang and Spearman to have n2 equal to 0 as disclosed in Wang to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Wang provides guidance that the thiol-based HA polymers can modified such that all of the acrylated HA is converted to the thiol group, as indicated by n2 equaling 0.
Claim(s) 29 is rejected under 35 U.S.C. 103 as being unpatentable over Wang (US20230021037A1 in PTO-892, effective filing date of 11/18/2019) in view of Spearman et al. (J Biomed Mater Res A, 2020 in PTO-892), as applied to claim 26 above, and further in view of Hahn et al. (US20070134334A1 in PTO-892).
The combined teachings of Wang and Spearman are as described above and teach the chemically modified HA as recited in instant claim 26 as discussed above.
The combined teachings, however, do not teach that other groups on hyaluronic acid are chemically modified or crosslinked.
Hahn discloses crosslinked polysaccharide microparticles such as hyaluronic acids and methods of preparing thereof for sustained-release formulations of drugs, proteins, or peptides (Abstract).
Hahn discloses that the polysaccharide derivative used is not limited as long as it is crosslinkable and further discloses that examples including HA derivatives having a crosslinkable functional group such as mercapto, methacryl, acryl, hydrazides, and others (paragraph 0050).
Hahn illustrates their HA derivatives as shown in Formula I (paragraph 0063) shown below:
PNG
media_image5.png
511
825
media_image5.png
Greyscale
The R1 and Ra2-Ra6 represent modifications sites of the HA as disclosed in paragraphs 0065-0066).
Hahn discloses that the HA derivative can be prepared by introducing a hydrazide group on the amino group which can be then be further reacted with anhydrides such as methacrylic anhydride and others (paragraph 0077).
Hahn demonstrates in Examples 9-1 through 9-2 (paragraphs 0179-0182) and Example 10 (paragraphs 0183-0185) modifying the amino group with a hydrazine (HA-HZ Formula 6 – paragraph 0179) and then further reacting to attach a thio or methacrylate group (HA-HZ-SH or HA-HZ-MA Formula 7-8 paragraph 0181 and 0183).
It would have been prima facie obvious before the effective filing date of the claimed invention modified the HA hydrogel as disclosed by the combined teachings of Wang and Spearman by including additional macromers such as the HA-HZ-SH or HA-HZ-MA disclosed in Hahn to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the combined teachings of Wang and Spearman described above and Hahn teach forming crosslinked HA by incorporating thiol or methacrylate end groups on the HA, and both references further teach using their respective crosslinked HA for the same medical applications (drug delivery systems).
Conclusion
No claim is found allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID H CHO whose telephone number is (571)270-0691. The examiner can normally be reached M-F 8AM-5PM.
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, Scarlett Goon can be reached at 571-270-5241. 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. Visit https://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 USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
Prosecution Insights