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 Application
Applicants' arguments/remarks filed 08/21/2025 are acknowledged. Claims 16-17 and 24 are currently amended. Claim 19 is newly canceled. Claims 25-28, 30 and 32-33 are currently withdrawn. Claims 16-18, 20-24, 29, 31, 16-17 and 34-35 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment, filed 08/21/2025 and with respect to the applicant’s arguments/remarks:
the 35 U.S.C. § 103 rejection of Claims 19 has been withdrawn in view of the cancelation of the claim;
the 35 U.S.C. § 103 rejection of Claims 16, 18-20-23, 29, 31 and 34-35, over Altman et al. and Gavard-Molliard has been withdrawn in view of the amendment of the claims 16 and 17;
the 35 U.S.C. § 103 rejection of Claims 16 and 17 and 24 over Altman et al., Gavard Molliard and Kettenberger et al. has been withdrawn in view of the amendment of the claims 16 and 17.
Modified Rejections
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 non-obviousness.
Claim(s) 16-18, 20-23, 29, 31, 16-17 and 34-35 is/are rejected under 35 U.S.C. 103 as being obvious by Altman et al. (US 12296067 B2)
Claims 16-18, 20-21 and 23,
Altman et al. teach in some embodiments, a tissue filler disclosed is injectable. (Col. 2, lines 24-25), comprising an organic compound and/or an inorganic compound. (Col. 5, lines 42-44).
The inorganic compound comprises calcium hydroxyapatite. (Col. 5, lines 42-44). (A).
In one embodiment, the invention relates to a biocompatible tissue filler comprising: a glycosaminoglycan selected from the group consisting of hyaluronic acid (HA). (Col. 6, lines 16-18). (B). In some embodiments, all of the HA is non-crosslinked. (Col. 12, lines 23-24, 33-34, or 47-48; or Col. 44, lines 36-37).
In some embodiments, the HA incorporated (Col. 93, line 67) in the tissue fillers described has a high molecular weight (e.g., an HA molecular weight of about 1 MDa to about 4 MDa). (Col. 94, lines 2-3). (B1).
In some embodiments, the dermal fillers are made by a process described by using HA having a low MW of about 50 kDa, about 100 kDa. (Col. 42, lines 36-38). (B2).
In some embodiments, the dermal fillers are made by a process described by using HA having a MW of between about 5 kDa and about 5 MDa. (Col. 42, lines 32-34). (B comprising a combination of components B1 and B2). Any of the above MW of HA can be mixed with any other of the above MW of HA, in any possible proportion. In some embodiments, a dermal filler is made by mixing a high MW HA with a low MW HA. (Col. 42, lines 61-65).
In some embodiments, a composition of the invention comprises a carrier phase. (Col. 46, lines 3-4). Potential carriers could include protein solutions, gels composed of polymers including proteins, glycoproteins, proteoglycans, or polysaccharides. (C). (Col. 46, lines 21-25).
In one embodiment, the invention relates to a biocompatible tissue filler comprising: an anesthetic agent. (Col. 3, line 61– Col. 4, line 1). (D).
Additional Agents: In some embodiments, the tissue fillers include an active agent, different from anesthetic agents, can be one or more of enzyme inhibitors, medicinal neurotoxins, antioxidants, anti-infective agents, anti-inflammatory agents, vasodilators, ultraviolet (UV) light blocking agents, dyes ( e.g., tattoo dye, ink or pigment), a reflective agent, hormones, immunosuppressants, and combinations thereof. (Col. 6, lines 7-12). In some embodiments, the tissue fillers include an active agent at a concentration, by weight, of 0.01%-50%. (Col. 163, lines 28-44 – Col. 164, lines 32-46). (E).
In some embodiments, the concentration of calcium hydroxyapatite is between about 0.001 % and about 5%. (Col. 5, lines 54-56).
In an embodiment, the percent HA by weight in the tissue filler composition is less than 99%-0.1% (Col. 94, lines 20-67-Col. 95 lines 1-38). In an embodiment, the percent HA by weight in the tissue filler composition is greater than 0.1%- 98%. (Col. 95, lines 39-67 – Col. 96, lines 1-56). With these concentrations of calcium hydroxyapatite and HA, it would be obvious that they are within the range of from 1000:1 to 1:10, 1000:1 to 1:1,or 2:1 to 1:1.
With regard to claim 22,
Altman et al. teach in some embodiments that the invention relates to a tissue filler further comprising an organic compound and/or an inorganic compound. In some embodiments, the inorganic compound comprises calcium hydroxyapatite. In some embodiments, the calcium hydroxyapatite is formulated as particles having a diameter between about 1 µm and about
100 µm, between about 1 µm and about 10 µm, between about 2 µm and about 12 µm, between about 3 µm and about 10 µm, between about 4 µm and about 15 µm, between about 8 µm and about 12 µm, between about 5 µm and about 10 µm, between about 6 µm and about 12 µm, between about 7 µm and about 20 µm, between about 9 µm and about 18 µm, or between about 10 µm and about 25 µm. (Col. 5, lines 42-54).
With regard to claim 23,
Altman et al. teach in some embodiments, a composition of the invention comprises a carrier phase. Useful carriers include any physiologically tolerable material which improves upon extrudability or intrudability of the hydrogel through a needle or into a target host environment. Potential carriers could include but are not limited to physiological buffer solutions, serum, other protein solutions, gels composed of polymers. (Col. 46, lines 3-4 and lines 23-25).
With regard to claim 29,
Altman et al. teach hyaluronic acid (hyaluronan) is a glycosaminoglycan that is distributed throughout the body and is found in connective and epithelial tissues. Due to its biocompatibility and structural benefits, it is a useful component in medical devices and implantable materials. Soft tissues of the human body owe their structures in part to an extracellular matrix that includes collagen, elastin, and glycosaminoglycan. Soft tissue defects may occur, which distort, deform, or otherwise alters soft tissue structures. Such structure may be restored through the use of tissue fillers that may be deposited at the defect site remedy the
defect. For example, tissue fillers may be placed at the site of a facial wrinkle to remedy the wrinkle. However, new tissue fillers are needed in the field that remedy a number of tissue defects while providing tunable properties, which may allow for tailoring of the tissue filler
to the specific tissue defect. (Col. 1, lines 11-28).
With regard to claim 31
Altman et al. teach in some embodiments, a composition of the invention comprises a carrier phase. (Col. 46, lines 3-4). Potential carriers could include but are not limited to polysaccharides (Col. 46, lines 21, 25). Suitable biocompatible polymers include polysaccharides (e.g., HA, chitosan, chondroitin sulfate, alginate, carboxymethylcellulose), poly( ethyleneglycol), poly(lactic acid), poly (hydroxyethylmethacrylate ), poly(methylmethacrylate ),
With regard to claims 34 and 35
Altman et al. teach in some embodiments, the condition treated by the tissue fillers may include a soft tissue condition. Soft tissue conditions include, augmentations, reconstructions, diseases, disorders, defects, or imperfections of a body part, region or area: a face, skin, lip, urethra defect, breast, cheeks, arm, hand, shoulder, back, torso, abdomen, buttocks, leg, calves, foot, eye, genitals; urinary incontinence, fecal incontinence, other forms of incontinence; and gastroesophageal reflux disease. (Col. 188, lines 13-53).
Claim(s) 16 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Altman et al. (US 12296067 B2), in view of Gavard-Molliard (US 20180193232 A1).
The teachings of Altman et al. are described in the rejection above.
Altman et al. teach in some embodiments, a tissue filler disclosed is injectable. (Col. 2, lines 24-25), comprising an organic compound and/or an inorganic compound. (Col. 5, lines 42-44).
The inorganic compound comprises calcium hydroxyapatite. (Col. 5, lines 42-44). In some embodiments, the calcium hydroxyapatite is formulated as particles having a diameter between about 1 µm and about 100 µm. (Col. 5, line 45-47). (A).
In one embodiment, the invention relates to a biocompatible tissue filler comprising: a glycosaminoglycan selected from the group consisting of hyaluronic acid (HA). (Col. 6, lines 16-18). (B). In an embodiment, the percent HA by weight in the tissue filler composition is less than 99%-0.1% (Col. 94, lines 20-67-Col. 95 lines 1-38). In some embodiments, all of the HA is non-crosslinked. (Col. 12, lines 23-24, 33-34, or 47-48; or Col. 44, lines 36-37).
In some embodiments, the HA incorporated (Col. 93, line 67) in the tissue fillers described has a high molecular weight (e.g., an HA molecular weight of about 1 MDa to about 4 MDa). (Col. 94, lines 2-3). (B1).
In some embodiments, the dermal fillers are made by a process described by using HA having a low MW of about 50 kDa, about 100 kDa. (Col. 42, lines 36-38). (B2).
In some embodiments, the dermal fillers are made by a process described by using HA having a MW of between about 5 kDa and about 5 MDa. (Col. 42, lines 32-34). (B). B comprises a combination of components B1 and B2. Any of the above MW of HA can be mixed with any other of the above MW of HA, in any possible proportion. In some embodiments, a dermal filler is made by mixing a high MW HA with a low MW HA. (Col. 42, lines 61-65). Because B1 and B2 can be mixed in any possible proportion, it would be obvious that they include B1 50-100% by weight and B2 0-50% by weight.
In some embodiments, a composition of the invention comprises a carrier phase. (Col. 46, lines 3-4). Potential carriers could include protein solutions, gels composed of polymers including proteins, glycoproteins, proteoglycans, or polysaccharides. (C). (Col. 46, lines 21-25). Tissue filler comprising silk protein or silk protein fragments (SPF). In some embodiments, the silk protein is silk fibroin. (Col. 7, lines 7-8). Silk protein, silk protein fragments or silk fibroin can be carrier. In some embodiments, the percent SPF content, by weight, in the tissue fillers described herein is at least 0.01 % - 99.9%. (Col. 57, lines 32-67-Col. 58, lines 1-29).
In one embodiment, the invention relates to a biocompatible tissue filler comprising: an anesthetic agent. (Col. 3, line 61– Col. 4, line 1). (D). In certain embodiments, the tissue fillers
can include one or more anesthetic agents in an amount effective to ameliorate or mitigate pain
like lidocaine or others. In some embodiments, the tissue fillers described herein may include lidocaine or other anesthetic at a concentration, by weight, of at least 0.01 %-10%. (Col. 166, lines 4-27).
Additional Agents: In some embodiments, the tissue fillers include an active agent, different from anesthetic agents, can be one or more of enzyme inhibitors, medicinal neurotoxins, antioxidants, anti-infective agents, anti-inflammatory agents, vasodilators, ultraviolet (UV) light blocking agents, dyes ( e.g., tattoo dye, ink or pigment), a reflective agent, hormones, immunosuppressants, and combinations thereof. (Col. 6, lines 7-12). In some embodiments, the tissue fillers include an active agent at a concentration, by weight, of 0.01%-50%. (Col. 163, lines 28-44 – Col. 164, lines 32-46). (E).
Altman et al. do not teach (A) 10 to 80% by weight, referred to dry matter, based on the composition, of one or more types of calcium hydroxyapatite particles having a mean particle size of 1 to 150 µm as component A.
Gavard Molliard teaches an injectable sterile aqueous formulation, ready-to-use, resorbable, used for aesthetic purposes as a particulate, cohesive, viscoelastic gel comprising
ii) hydroxyapatite, at a concentration of between 5% and 60% (mass/volume), said
hydroxyapatite being in the form of particles with an average size of less than or equal to 200 µm; (Abs). (A).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to prepare an injectable composition comprising
Calcium Hydroxyapatite, with a mean diameter between about 1 µm and about 100 µm.
hyaluronic acid, the percent HA by weight in the tissue filler composition is less than 99%-0.1%. The dermal fillers are made by a process described by using HA having a MW of between about 5 kDa and about 5 MDa. In some embodiments, the HA incorporated (Col. 93, line 67) in the tissue fillers described has a high molecular weight (e.g., an HA molecular weight of about 1 MDa to about 4 MDa). In some embodiments, the dermal fillers are made by a process described by using HA having a low MW of about 50 kDa, about 100 kDa. B comprises a combination of components B1 and B2. Any of the above MW of HA can be mixed with any other of the above MW of HA, in any possible proportion. In some embodiments, a dermal filler is made by mixing a high MW HA with a low MW HA. In some embodiments, all of the HA is non-crosslinked. In some embodiments, all of the HA is non-crosslinked.
In some embodiments, a composition of the invention comprises a carrier, which include a protein, like silk protein fragments, with 0.01 % - 99.9% by weight.
In one embodiment, the invention relates to a biocompatible tissue filler comprising: an anesthetic agent, like lidocaine or other anesthetic at a concentration, by weight, of at least 0.01 %-10%.
In some embodiments, the tissue fillers include an active agent, different from anesthetic agents, can be one or more of enzyme inhibitors, medicinal neurotoxins, antioxidants, anti-infective agents, anti-inflammatory agents, vasodilators, ultraviolet (UV) light blocking agents, dyes ( e.g., tattoo dye, ink or pigment), a reflective agent, hormones, immunosuppressants, at a concentration, by weight, of 0.01%-50%. All taught by Altman et al., and A, hydroxyapatite, at a concentration of between 5% and 60%, talk by Gavard Molliard, since they have proven it would be possible to do so.
Response to Arguments
Rejections Under 35 U.S.C. § 103
Altman in view of Gavard-Molliard
Applicant argues that Altman fails to disclose one or more pharmaceutically acceptable additives other than components A, B, C, and D as component E, wherein the weight ratio of components A: B range from 1000:1 to 1:10. Altman and Gavard-Molliard, alone or in combination, do not teach or suggest each and every feature of the instant claims. Altman fails to teach or suggest at least the recited features of an injectable composition comprising hyaluronic acid comprising one or more types of non-crosslinked high--molecular weight hyaluronic acid of a mean molecular weight in the range of from 1 to 5 MDa and one or more types of non-crosslinked low--molecular weight hyaluronic acid of a mean molecular weight in the range of from 5 to 100 kDa in one single formulation, as recited in the instant claims. Further, Altman fails to teach or suggest one or more pharmaceutically acceptable additives other than components A, B, C, and Das component E, wherein the weight ratio of components A: B range from 1000:1 to 1:10.
Applicant's arguments have been fully considered and they are persuasive according to the previous Office Action of the Non-Final Rejection. However, with the amendment of claims 16 and 24, limiting HA to only non-crosslinked, the teachings of Gavard Molliard and Kettenberger et al. can’t apply for non-crosslinked HA. However, Altman does. Please see the modified rejection of claims 16 and 24 above. In short, Altman teaches two group of HA, one with high molecular weights of B1 and one with low MW of B2 and in some embodiments, all of the HA is non-crosslinked and Any of the above MW of HA can be mixed with any other of the above MW of HA, in any possible proportion. In some embodiments, a dermal filler is made by mixing a high MW HA with a low MW HA. And with these reasons, B1 and B2 would be non-crosslinked and would be mixed and the ratio of A and B would be in the range of applicant’s limitation.
Applicant argues that Applicant notes that the assertion that Gavard-Molliard teaches or suggests a ratio of hydroxyapatite to hyaluronic acid is in the range of 60:1 to 5:4 could not be found in the reference and kindly requests clarification of the ranges cited.
Applicant's question about 60:1 to 5:4 has been fully considered, but it is moot now since the rejection is modified in this new office action. Gavard-Molliard’s teaching is no long used. But, that range was based on percentages of hyaluronic acid (HA) 1-4% and hydroxyapatite (HD) 5-60% to highest % of HD 60% vs. lowest HA 1% and lowest % of HD 5% vs highest % of HA 4%.
Applicant argues that Gavard-Molliard does not cure the deficiencies of Altman. A person of ordinary skill in the art would not have looked to Gavard-Molliard to cure the deficiencies of Altman, at least because Gavard-Molliard also does not teach each and every feature of the instant claims. Moreover, Gavard-Molliard states that, "[t]he inventor has shown that in the following examples that the formulation according to the invention based on crosslinked HA should have specific properties. If such is not the case (see the examples with non-crosslinked HA or with crosslinked HA not having the claimed structure), the hydroxyapatite particles are not properly maintained within the matrix and may therefore diffuse relatively easily out of the gel, which implies a loss of volume at the treated area (i.e. a loss of efficiency) and possible complications because of this migration causing safety problems."
Applicant's arguments have been fully considered and they are persuasive according to the previous Office Action (OA) of the Non-Final Rejection (NFR). However, with the amendment of claims 16 and 24, limiting to only non-crosslinked HA, Gavard-Molliard is no long applied in this OA in claim 16. The OA is modified with only claim 16 to only Altman’s teachings as explained above and more details in the OA above.
Applicant argues that the present application (see pg. 7, 4th par., and Tables 2 and 3) demonstrates that the specific B1 and B2 combination yields unexpected technical benefits, particularly enhanced Collagen Ill expression, which is not observed when either non-crosslinked high-molecular weight hyaluronic acid and a non-crosslinked low-molecular-weight hyaluronic acid form is used alone. Moreover, the use of non-crosslinked hyaluronic acid forms avoids the need for xenobiotic activators and undesired covalent bonding, offering further technical advantages not disclosed or suggested by the cited references/
Applicant's arguments have been fully considered and they are persuasive according to the previous Office Action (OA) of the Non-Final Rejection (NFR). However, with this modified OA, Altman teaches all options of the composition, including both crosslinked and non-crosslinked HA and one with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results.
Altman in view of Gavard-Molliard and further in view of Kettenberger et al.
Applicant argues that While Altman mentions non-crosslinked hyaluronic acid and various molecular weights, it fails to disclose a single composition containing both high- and low-molecular-weight non-crosslinked forms together in respective molecular weight ranges. Kettenberger discloses a two-phase formulation, but the hyaluronic acid in the first phase is explicitly crosslinked and seems to teach away from being used to modify Altman and cure any deficiencies therein. In Example 2, Kettenberger is alleged to disclose a composition in which the first phase contains tricalcium phosphate particles and a salt of hyaluronic acid with a molecular weight of 2 MDa, and the second phase contains tricalcium phosphate and a salt of
hyaluronic acid with a molecular weight of 50 kDa, the two phases being mixed in a 4:1 ratio and subsequently heat sterilized.
Applicant's arguments have been fully considered and they are persuasive according to the previous Office Action (OA) of the Non-Final Rejection (NFR), with Kettenberger, who teaches first phase is explicitly crosslinked. However, with this modified OA, Kettenberger is removed. Altman teaches all options of the composition, including both crosslinked and non-crosslinked HA. Even though Altman does not disclose a single composition containing both high- and low-molecular-weight non-crosslinked forms together in respective molecular weight ranges. However, "a reference is presumed operable until applicant provides facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980)".
Conclusion
Applicants' 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 extension fee 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 date of this final action.
Correspondence
No claim is allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615