DETAILED ACTION
Status of the Claims
Claims 1 and 8-26 are pending in the instant application. Claims 15-22, 25 and 26 have been withdrawn based upon Restriction/Election. Claims 1, 8-14, 23 and 24 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 12/20/2018 the filing date of document KR10-2018-0166747.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 8-14, 23 and 24 remain rejected under 35 U.S.C. 103 as being unpatentable over D1 (KR 10-2015-0029578 A; published March 2015; K-PION Korean-language/English-language machine translation of KR 10-2015-0029578 relied on herein) in view of Yang et al. (“Determination of modification degree in BDDE-modified hyaluronic acid hydrogel by SEC/MS,” 2015, ELSEVIER; Carbohydrate Polymers, Vol. 131, pp. 233-239); JUNG (US 2018/0344896; published 06-DEC-2018); Edsman et al. (“Gel Properties of Hyaluronic Acid Dermal Fillers,” 2012; Wiley; Dermatologic Surgery, Vol. 38, Issue 7pt2, pp. 1170-1179) and LIU (US 2013/0123210; published May, 2013).
Applicants Claims
Applicant claims “A filler comprising a hyaluronic acid hydrogel including hyaluronic acid, hyaluronic acid salt or crosslinked hyaluronic acid,
wherein a ratio of lift capability of a unit content (w/w%) of the hyaluronic acid contained in the filler relative to a modification degree (mol%) is 60 to 180 ((Pa* N/(w/w)%)/mol%) in accordance with Equation 3 below:
[Equation 3] Lift Capability per Hyaluronic Acid Unit Content and Modification Degree = A/B wherein, A represents a value obtained by dividing the lift capability represented by Equation 1 below by the unit content (w/w%) of hyaluronic acid contained in the filler, and B represents a modification degree represented by Equation 2 below:
[Equation 1] Lift Capability (Pa*N) = Storage Elastic Modulus X Cohesive Force
[Equation 2] Modification degree (mol%) = (mole number of total crosslinking agent bonded to the entire hyaluronic acid molecule / the number of moles of total (N-acetyl-D-glucosamine + D- glucuronic acid)) * 100, wherein the cohesive force is measured with an Oscillatory and Rotational Rheometer at an initial gap position of 1.0 mm and final gap position of 15 mm, with a speed of 0.93 mm/s, at 25 °C and measuring geometry of 25 mm plate/plate, wherein the crosslinked hyaluronic acid is obtained by crosslinking a hyaluronic acid having a molecular weight of 2,500,000 Da to 3,500,000 Da, or a salt thereof, and wherein the Modification degree is 3 to 4 mol%, wherein the A value is 200 to 650 Pa*N/(w/w)% and wherein the cohesive force is 1.0 to 1.7 N as measured by a Tack test, and wherein the Storage Elastic Modulus is 400 to 800 Pa (instant claim 1).
Election of Species: (a) crosslinked hyaluronic acid (no average molecular weight specified; the concentration based on the total weight of the mixture of HA and the alkaline aqueous solution not specified), and (b) BDDE (1,4-butandiol diglycidyl ether) as the crosslinking agent (the concentration relative to the weight of HA not specified).
Determination of the scope
and content of the prior art (MPEP 2141.01)
D1 discloses a method for preparing a hyaluronic acid cross-linked into a high-density reticulated structure and a wrinkle reducing filler comprising same, the method comprising the steps of: linearizing a polymer hyaluronic acid by dissolving same in an alkaline aqueous solution and cross-linking and reacting same by means of a cross-linking agent to obtain a hydrogel; cutting the hydrogel; swelling the hydrogel by means of a buffer solution; grinding the swollen hydrogel; and sterilizing the hydrogel (see claims 1, 10 and 13).
D1 discloses that: “according to the present invention is cross-linked to the network structure maximizes the viscosity and cohesion and the durability in vivo is increased and the biocompatibility is excellent at the same time the injection pressure is low and it can be effectively used for the filler for the removing wrinkle and treatment of osteoarthritis the etc.” (p. 4, para. 46).
D1 discloses that: “In 20℃ in 1.0% NaOH of 100 mL the high molecular hyaluronic acid […] of 10 g after it melted for 8 hours and the hyaluronic acid was linearized it put and BDDE was reacted in 10 Mol% to the cross-linking agent about the hyaluronic acid in 45℃ for 4 hours.” [emphasis added](p. 4, para. 50)(instant claim 1 crosslinked hyaluronic acid, instant claims 6-9).
D1 discloses that: “Another object of the present invention is to provide the filler for the removing wrinkle including the hyaluronic acid in which the high intensity is cross-linked to the network structure.” [emphasis added](p. 2, paragraph 10)(instant claims 14 & 24).
D1 teaches the inclusion of lidocaine (p. 5, paragraph 53)(instant claims 11-12), and discusses removal of residual crosslinking agent (p. 3, paragraph 32)(instant claim 10). D1 teaches filling into syringe (i.e. a pre-filled syringe)(p. 3, paragraph 40)(instant claims 13 & 23).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of D1 is that D1 does not expressly teach the feature wherein, in a hydrogel filler, the lifting characteristic ratio relative to a hyaluronic acid unit content (w/w%) comprised in the filler according to mathematical formula 3 is 60-180 ((Pa*N/(w/w)%)/mol%).
However, (1) D1 discloses the feature wherein the hyaluronic acid hydrogel exhibits excellent viscoelasticity and maximized viscosity and cohesiveness (see paragraphs [0007] and [0040]), (2) according to the entire specification of the application invention, with respect to a numerical range being satisfied in accordance with mathematical formula 3, effectiveness of factors such as high cohesion, high elasticity, minimized deformation, maximized maintenance of hyaluronic acid molecules in the natural state and less immune responses and side effects induced thereby is only subjectively described, and there are no objective facts supporting the critical significance, and (3) the factors listed in (2) above are properties which are to be adjusted to an appropriate level when necessary by a person skilled in the art in a field relating to a filler comprising a hyaluronic acid. Therefore, the numerical range in accordance with mathematical formula 3 in claim 1 could appropriately be selected by a person skilled in the art in accordance with the purpose. (see Written Opinion of the International Searching Authority - English Language ‘Translation)(instant claims 1 “a ratio of lift capability of a unit of content (w/w%) of the hyaluronic acid contained in the filler relative to a modification degree (mol%) is 60-180”; “the A value is 200 to 650”; “the storage elastic modulus is 400 to 800 Pa and the cohesive force is 1.0 to 1.7 N”).
Yang et al. teaches that: “HA has excellent biocompatibility, high water retention capacity and viscoelasticity, which makes it suitable for various medical and cosmetic applications. Cosmetic injections of HA filler are known to be the most popular non-surgical procedure for patients […]. Combining HA powder with water forms a viscous solution of HA, which is known as free HA. If free HA was used as a dermal filler, it would be rapidly eliminated from the injection site by drainage or degradation pathways […]. Natural HA therefore is chemical modified by cross-linkers to improve the mechanical properties and prolong its duration in vivo […]. The modification creates a polymer network, transforming a viscous solution to a weak gel. HA gel imparts a physical and chemical barrier to deter drainage or degradation […].” (p. 233, §Introduction, 2nd paragraph). And that: “The two crosslinkers employed in HA dermal fillers currently in the market are 1,4-butanediol diglycidal ether (BDDE) and divinylsulfone (DVS) […] Both of them react to hydroxyl groups on HA chains and give similar outcomes: slowing down the drainage and degradation of dermal fillers injected into the skin. BDDE, one of diepoxide crosslinkers, has a widely application in many dermal filler products, like Restylanes® from Q-Med, JuvédermTM from Allergan and Modelisshape from Anteis. Diepoxides can react with the 6-hydroxylgroup of HA under alkaline conditions to form ether linkages […], 6-hydroxyl group can get a negative charge easily due to its optimal steric conformation in the sugar ring […]. The linear HA molecules can conjugate with BDDE in two ways: one ether linkage formed in a BDDE molecule which refers to pendent modification and two ether linkages formed which refers to cross-link modification (Fig. 2). Therefore three crosslinking parameters were defined as: degree of total modification (t-MOD), degree of cross-link modification (c-MOD), degree of pendent modification (p-MOD). Table 1 summarizes the definitions for three crosslinking parameters with examples of a hypothetical BDDE-modified HA segment.” (pp. 233-234, §Introduction, 3rd paragraph). And that: “The main differences between dermal filler products in the market are the source of HA, concentration, particle size of gel, degree of modification. Currently HA used in filler are mostly from the synthetic fermentation of bacteria. The concentration of HA has an important role in dermal fillers. Dermal fillers with high HA concentration tend to have better “volume” and longer duration in vivo […]. The degree of modification have a significant effect on the properties of a filler. Modification can potentially improve resistance to degradation, making for a longer lasting treatment, but increase the difficulty of injection. The hydrogel with higher t-MOD shows stronger and better resistance to enzyme, resulting a longer duration in vivo. On contrast, hydrogel with lower t-MOD is softer and degraded faster. Cross-link modification, as the effective modification type, dominantly strengthens the overall network of hydrogel, increasing the hardness and resistance to HAase. Hydrogels with same t-MOD but higher c-MOD shows much harder and better resistance to enzyme” (p. 234, col. 1, 2nd paragraph).
Yang et al. teaches the t-MOD (degree of modification of hyaluronic acid) in the range of about 2.4 to 4.9 % (see whole document, particularly Table 1 and accompanying text; Table 7, col. “t-MOD(%)”, and accompanying text)(instant claim 1, “wherein the Modification degrees is 3 to 4 mol%).
JUNG teaches hyaluronic acid having excellent viscoelasticity and being easily injectable (abstract, see whole document). JUNG teaches that: “Currently available hyaluronic acid fillers have a monophasic or biphasic nature. Monophasic fillers are entirely composed of homogeneous gel, and thus highly viscous, and are easy to inject and suitable for shaping delicate areas. Biphasic fillers are prepared as particles by passing the gel mass through a sieve, and are thus highly elastic and advantageous in maintaining shape and improving volume.” ([0004]). And that: “With this background, the present inventors studied to develop hyaluronic acid fillers having optimal viscoelasticity and surgical usability, and as a result, they have found that two or more hyaluronic acid gels having different phases are mixed by revolution/rotation at a particular speed to prepare a crosslinked hyaluronic acid composition having both monophasic and biphasic characteristics, thereby completing the present invention.” [emphasis added]([0007]).
JUNG teaches that: “The hyaluronic acid may have a molecular weight of 100,000 Da to 5,000,000 Da, but is not limited thereto.” [emphasis added](instant claim 1, “a hyaluronic acid having a molecular weight of 2.500,000 Da to 3.055.000 Da”). And that: “The hyaluronic acid composition for tissue restoration may be filled into a syringe to be injected into the skin layer.” ([0049])(instant claims 13 & 23).
Regarding the amount of crosslinking agent remaining being less than 0.5 ppm (residual crosslinking agent), it would have been prima facie obvious to fully utilize the crosslinking agent thereby including minimal residual crosslinking agent in the filler because the crosslinking agent is a cost-input, and residual crosslinking agent is wasted money.
Edsman et al. teaches the gel properties of hyaluronic acid dermal fillers (see whole document) including the Gel Strength (p. 1171, col. 1, last paragraph) as measured by rheological properties (p. 1171, col. 2). Edsman et al. teaches that: “When cross-links between the polymer chains are introduced, a three-dimensional network of the gel is formed. Just like solutions, gels will have viscous and elastic properties, but the elastic properties dominate over the whole frequency range as a result of the network (Figure 3), which means that the deformation that occurs because of forces of long and short duration will be regained when the force is removed. A strong gel has a high elasticity, meaning that the response to deformation is mainly elastic. Weak gels have a lower elastic modulus, and the ratio of elastic to viscous behavior is usually lower than for a strong gel. Factors that affect the rheological properties of gels are, for example, the polymer concentration and the cross-linking density (including chemical cross-links and entanglements). A higher concentration and a higher cross-linking density render a higher elastic modulus of the gel.” [emphasis added](p. 1172, col. 1, last paragraph)(instant claim 4, optimization of the storage elastic modulus).
LIU teaches dermal filler compositions including antioxidants (see whole document), and particularly including a high molecular weight hyaluronic acid (about 1,000,000 Da, about 1,500,000 Da, about 2,000,000 Da, about 2,500,000 Da, about 3,000,000 Da, about 3,500,000 Da, about 4,000,000 Da, about 4,500,000 Da, or about 5,000,000 Da.), and “wherein the hyaluronic acid is crosslinked with BDDE. In this embodiment, the degree of conjugation may be between about 3 mol % and about 15 mol %” ([0077])(instant claim 1, “hyaluronic acid having a molecular weight of 2,500,000 Da to 3,500,000 Da”).
LIU teaches that: “Cohesiveness is affected by, among other factors, the molecular weight ratio of the initial free glycosaminoglycan polymer, the degree of crosslinking of glycosaminoglycan polymers, the amount of residual free glycosaminoglycan polymers following crosslinking, and the pH of the hydrogel composition.” ([0094])(instant claim 4, cohesive force optimization). LIU teaches the storage elastic modulus ([0080]) including the range of about 400 Pa to about 800 Pa ([0082]).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a hyaluronic acid (HA) crosslinked dermal filler that exhibits excellent viscoelasticity and maximized viscosity and cohesiveness, as suggested by D1 and JUNG, and including BDDE as the crosslinking agent (D1, JUNG, LIU) such that the HA dermal filler network structure maximizes the viscosity and cohesion and the durability in vivo is increased and the biocompatibility is excellent at the same time the injection pressure is low and it can be effectively used for the filler for the removing wrinkle, as suggested by D1. Additionally, the factors affecting the storage elastic modulus are taught by Edsman et al. (HA concentration & crosslinking density) and the factors affecting the cohesivity are taught by LIU (molecular weight ratio of the initial free glycosaminoglycan polymer, the degree of crosslinking of glycosaminoglycan polymers, the amount of residual free glycosaminoglycan polymers following crosslinking, and the pH of the hydrogel composition), therefore it would have been prima facie to optimize the storage elastic modulus (i.e. gel strength) and the cohesivity (i.e. tendency of the gel to stick together and hold its shape under stress) in order to produce the best viscoelastic crosslinked HA dermal filler.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because the prior art teaches the same constituent ingredients and the same properties for crosslinked hyaluronic acid dermal fillers, as well as the properties affecting the storage elastic modulus (i.e. gel strength) and the cohesivity (i.e. tendency of the gel to stick together and hold its shape under stress). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 06/18/2025 have been fully considered but they are not persuasive.
Applicant argues that: “D1, alone or in combination with Yang, Jung, Edsman, and Liu, fails to teach or suggest the combination of features recited in amended claim 1. Claim 1, as amended, is directed to a filler comprising a hyaluronic acid hydrogel including a combined parameter that determines the physical properties of a filler having both high elasticity and cohesivity. Specifically, the claimed invention recites "Lift Capability per Hyaluronic Acid Unit Content and Modification Degree= A/B," obtained by combining the combined parameters of Lift Capability and the Modification Degree. Furthermore, the claimed invention includes a specific numerical range defined as A/B = 60-180 Pa-N/(w/w%)/mol%. That is, unlike the cited references, which merely list values of individual factors related to the filler, the claimed invention comprises the combined parameter A/B, which simultaneously determines the filler's high elasticity and cohesivity. By using this combined parameter, filler comprising a hyaluronic acid hydrogel according to the claimed invention overcomes the trade-off among elasticity, cohesivity, and crosslinker amount in conventional fillers.” (p. 8). Applicant argues that: “A person of ordinary skill in the art would not have been motivated to modify D1 to arrive at the claimed invention with a reasonable expectation of success, even considering Yang, Jung, Edsman and Liu. Dl merely discloses a BDDE-crosslinked HA gel and does not disclose Lift Capability or the Modification Degree, nor does it recognize their effect on filler performance. Yang fails to remedy the deficiencies of D1, as Yang merely states that a higher Modification Degree increases the gel's resistance to degradation and does not recognize any need for a combined parameter involving both the Lift Capability and the Modification Degree. In particular, Yang states that a gel with a higher Modification Degree is stronger and longer lasting and thus simply teaches increasing the Modification Degree (p. 234, left column), which fails to provide any guidance or suggestion how to modify Dl to arrive at the claimed invention, which requires a ratio between the Lift Capability and the Modification Degree in the range of 60-180 Pa-N/(w/w%)/mol%.” (Paragraph bridging pp. 8-9).
In response the examiner maintains that: It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a hyaluronic acid (HA) crosslinked dermal filler that exhibits excellent viscoelasticity and maximized viscosity and cohesiveness, as suggested by D1 and JUNG, and including BDDE as the crosslinking agent (D1, JUNG, LIU) such that the HA dermal filler network structure maximizes the viscosity and cohesion and the durability in vivo is increased and the biocompatibility is excellent at the same time the injection pressure is low and it can be effectively used for the filler for the removing wrinkle, as suggested by D1. Additionally, the factors affecting the storage elastic modulus are taught by Edsman et al. (HA concentration & crosslinking density) and the factors affecting the cohesivity are taught by LIU (molecular weight ratio of the initial free glycosaminoglycan polymer, the degree of crosslinking of glycosaminoglycan polymers, the amount of residual free glycosaminoglycan polymers following crosslinking, and the pH of the hydrogel composition), therefore it would have been prima facie to optimize the storage elastic modulus (i.e. gel strength) and the cohesivity (i.e. tendency of the gel to stick together and hold its shape under stress) in order to produce the best viscoelastic crosslinked HA dermal filler.
Applicant argues that: “Jung also fails to remedy the deficiencies of D1 and Yang because Jung merely relies on mixing two types of fillers. Specifically, Jung discloses a crosslinked hyaluronic acid composition having characteristics of both monophasic and biphasic fillers, which is prepared by simply mixing two or more hyaluronic acid gels having different phases (see Paragraphs [0007], [0008], and [0013] of Jung). In contrast, a filler comprising a hyaluronic acid hydrogel according to the claimed invention has improved filler properties by controlling the A/B parameter regardless of whether two types of fillers are mixed, which is not suggested by the cited references, alone or in combination. Jung does not teach or propose any combined design of physical property variables such as storage modulus, stretching resistance, and the Modification Degree.” (p. 9, 2nd paragraph).
In response the examiner argues that Applicants claims are generic to including two or more species of crosslinked hyaluronic acid polymers. MPEP §2111.03 - The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. [emphasis added]. Yang et al. teaches that “The main differences between dermal filler products in the market are the source of HA, concentration, particle size of gel, degree of modification.” (p. 234, col. 1, 2nd paragraph). Yang et al. makes clear that BDDE is one of the most commonly used crosslinkers in HA dermal fillers (p. 233, col. 2, 2nd paragraph). Therefore, the claimed invention is simply a filler comprising hyaluronic acid having a molecular weight of 2,500,000 Da to 3,500,000 Da, and crosslinked with BDDE (instant claim 9), wherein the modification degree is 3 to 4 mol%.
Applicant further argues that: “Edsman and Liu cannot remedy the deficiencies of D1, Yang, and Jung to teach or suggest the claimed invention as a whole. Edsman merely suggests a relationship between gel strength and Lift Capability, and fails to recognize any need to arrive at a combined parameter involving both the Lift Capability and the Modification Degree, let alone in the specifically claimed range of 60-180 Pa-N/(w/w%)/mol%. In particular, Edsman discloses using a strong gel, i.e., a gel having a high Lift Capability, to achieve the desired correction effect (p. 1177, right column). Thus, by merely suggesting an increase in Lift Capability, Edsman fails to provide any guidance or suggestion to modify Dl to arrive at the claimed invention, which is a hyaluronic acid hydrogel having the claimed ratio between Lift Capability and the Modification Degree, even when considering Yang and Jung. Liu merely provides the theoretical modification degree of BDDE, and only the degree of single bonding of AA2G (ascorbyl glucoside per HA unit) was provided (see paragraphs [0075] and [0132]). Thus, Liu merely lists individual variables, and fails to recognize the necessity of the A/B combination or the need to achieve high elasticity and high cohesivity simultaneously.” (paragraph bridging pp. 9-10).
In response the examiner argues that Yang et al. teaches that “The main differences between dermal filler products in the market are the source of HA, concentration, particle size of gel, degree of modification.” (p. 234, col. 1, 2nd paragraph). Yang et al. makes clear that BDDE is one of the most commonly used crosslinkers in HA dermal fillers (p. 233, col. 2, 2nd paragraph). Therefore, the claimed invention is simply a filler comprising hyaluronic acid having a molecular weight of 2,500,000 Da to 3,500,000 Da, and crosslinked with BDDE (instant claim 9), wherein the modification degree is 3 to 4 mol%. Indeed LIU teaches that originally naturally-occurring HA was used without crosslinking which lead to desired benefits but required frequent injections as naturally-occurring HA was prone to degradation ([0006]), and therefore crosslinked HA was used which also resulted in improved mechanical properties as the crosslinked HA’s were more solid substances and “because the more solid nature thereof improves the mechanical properties of the filler, allowing the filler to better lift and fill in skin region” ([0007]). LIU further teaches that: “Cohesiveness is affected by, among other factors, the molecular weight ratio of the initial free glycosaminoglycan polymer, the degree of crosslinking of glycosaminoglycan polymers, the amount of residual free glycosaminoglycan polymers following crosslinking, and the pH of the hydrogel
composition.” ([0094]). One of ordinary skill in the art would have been motivated to provide a crosslinked hyaluronic acid filler with good mechanical properties by selecting the appropriate molecular weight of the HA, and BDDE crosslinking degree (t-mod, per Yang et al.).
Applicant further argues that: “In contrast to the cited references, a filler according to the claimed invention provides both high elasticity and cohesivity using only a small amount of crosslinking agent, without mixing different types of fillers, which is not taught or suggested by the combination of references cited in the Office Action. For example, the "Lift Capability per Hyaluronic Acid Unit Content and Modification Degree" in the claimed invention was derived based on consideration of how the modification degree, lift capability, and molecular weight of hyaluronic acid should be balanced in order to produce a filler having excellent properties while using a relatively small amount of crosslinking agent. This parameter is not disclosed in any of the cited references. Furthermore, the amended Claim 1 defines specific ranges for lift capability per hyaluronic acid unit content and modification degree, the ratio of lift capability per unit content, the modification degree, the molecular weight of hyaluronic acid, and the cohesivity. None of the cited references provides a motivation to arrive at the claimed ranges with a reasonable expectation of success. Thus, Applicant submits that a prima facie case of obviousness has not been established for at least the foregoing reasons.” (p. 10, 2nd paragraph).
In response the examiner argues that Applicants are claiming a composition of matter which is a HA filler that is crosslinked with BDDE (instant claim 9) to a degree of modification of 3 to 4 mol%. The prior art is clear that the molecular weight of the HA and the degree of crosslinking affects the mechanical properties of the resulting filler. The prior art clearly teaches HA’s having the same molecular weight and suggest the same degree of modification using BDDE (t-mod), therefore it would have been within the ordinary level of skill to modify the degree of modification and/or molecular weight with a predictable improvement in the filler mechanical properties such as the (storage) elastic modulus, the cohesiveness, and/or the lift and fill capability in use as a dermal filler. Edsman et al. teaches the gel properties of hyaluronic acid dermal fillers “A strong gel has a high elasticity, meaning that the response to deformation is mainly elastic. Weak gels have a lower elastic modulus, and the ratio of elastic to viscous behavior is usually lower than for a strong gel. Factors that affect the rheological properties of gels are, for example, the polymer concentration and the cross-linking density (including chemical cross-links and entanglements). A higher concentration and a higher cross-linking density render a higher elastic modulus of the gel.” [emphasis added](p. 1172, col. 1, last paragraph)(instant claim 4, optimization of the storage elastic modulus). Additionally, Yang et al. teaches that: “The hydrogel with higher t-MOD shows stronger and better resistance to enzyme, resulting a longer duration in vivo. On contrast, hydrogel with lower t-MOD is softer and degraded faster.” (p. 234, col. 1, lines 12-15).
Applicant further claims unexpected results, and particularly that: “Applicant submits concurrently herewith a declaration by Cheol Jang, an inventor of the subject application, "the Jang Declaration," demonstrating the unexpected results of the claimed invention over the closest prior art, D1. Specifically, the rheological properties of Examples 1 and 2 disclosed in the originally filed specification were analyzed using a rheometer and compared with the elastic properties of a commercially available filler formulation including hyaluronic acid hydrogel shown as Comparative Example 1 (Juvéderm Volift with Lidocaine) in the originally filed specification and New Samples 1 to 5 shown Table A of the Jang Declaration. See Jang Declaration, ¶¶ 15-17.” (paragraph bridging pp. 10-11). Applicant further argues that: “Only the fillers according to the claimed invention have physical properties suitable for facial lifting. Table A in the Jang Declaration compares fillers having various properties, demonstrating that when the storage modulus is too low, as in Samples 1-2, the filler cannot maintain its injected shape for a long time. Samples 1 and 2, where BDDE input is high and the reaction concentration is low, are similar to D1. Alternatively, when the storage modulus is too high, as in Samples 3-5, tissue reactions may be induced upon dermal administration. Samples 3-5 are cases where BDDE input is high and the reaction concentration is high, the resulting physical properties are too strong raising concerns of tissue reaction and making it unsuitable as a soft tissue filler. The Jang Declaration explains that commercially available fillers having a storage modulus exceeding 1,000 Pa are rarely found.” (paragraph bridging pp. 11-12). And that: “The Jang Declaration explains that in the manufacture of HA fillers, a large amount of crosslinker is used to improve rheological properties and durability, but an increased amount of crosslinker causes problems of toxicity and reduced biocompatibility. The Modification Degree (B) directly reflects the "amount of crosslinker used," and the amount of crosslinker used in Example 1 is about half that of Comparative Example 1.” (p. 12, 3rd paragraph). Applicant provides New Example A and “Notably, the modification degree of Example 1-which satisfies the conditions of Claim 1- was 56% of that of Comparative Example 1. This demonstrates that, despite using a smaller amount of crosslinker, the claimed invention achieves equivalent in vivo persistence and volume retention compared to the comparative example, without causing inflammation or adverse effects. The Jang Declaration explains that HA content (w/w%) is described in the specification and as shown in Table 1 in the specification of the subject application, the Modification Degree of Examples 1 and 2 is shown in the fifth row of Table 1 (3.3 and 3.5 mol%).” (p. 12, last paragraph). Applicant further argues that: “As shown in Figure A of the Jang Declaration, the filler of Example 1 with a smaller amount of crosslinker relative to Comparative Example 1 exhibited long-term persistence (1 year) comparable to that of Comparative Example 1. Example 1 also showed excellent biocompatibility without adverse effects such as inflammatory responses. Example 1 has a modification degree that is approximately 56% of that of Comparative Example 1 (i.e., a lower amount of crosslinker used); nevertheless, it shows a comparable level of in vivo
persistence. Moreover, approximately 50% of the initial volume in Example 1 was retained over a one-year period. Figure C further shows that Example 1 had improved histological scoring for a 12-month period relative to Comparative Example 1, demonstrating that the claimed invention can secure the desired high-performance filler properties without excessive use of crosslinker. […] Thus, despite using a smaller amount of crosslinker, the claimed invention achieves equivalent in vivo persistence and volume retention compared to the comparative example, without causing inflammation or adverse effects.” (p. 13, 1st paragraph). And that: “The Jang Declaration opines that the claimed invention provides a filler that simultaneously achieves a high cross-linking ratio, high elasticity, and high cohesivity with only a smaller amount of crosslinker than Dl, which would have been unexpected over the closest prior art, Dl. The showing of unexpected results must be based on comparisons with the closest prior art.” (p. 14, 1st paragraph). And that: “the specification and Jang Declaration demonstrate that the claimed invention would have been unexpected over the closest prior art, Dl, and successfully rebuts any alleged prima facie case of obviousness.” (p. 14, last paragraph).
In response the examiner argues that the instant claims are directed to “A filler comprising a hyaluronic acid hydrogel including hyaluronic acid, hyaluronic acid salt or crosslinked hyaluronic acid,
wherein a ratio of lift capability of a unit content (w/w%) of the hyaluronic acid contained in the filler relative to a modification degree (mol%) is 60 to 180 ((Pa* N/(w/w)%)/mol%) in accordance with Equation 3 below:
[Equation 3] Lift Capability per Hyaluronic Acid Unit Content and Modification Degree = A/B wherein, A represents a value obtained by dividing the lift capability represented by Equation 1 below by the unit content (w/w%) of hyaluronic acid contained in the filler, and B represents a modification degree represented by Equation 2 below:
[Equation 1] Lift Capability (Pa*N) = Storage Elastic Modulus X Cohesive Force
[Equation 2] Modification degree (mol%) = (mole number of total crosslinking agent bonded to the entire hyaluronic acid molecule / the number of moles of total (N-acetyl-D-glucosamine + D- glucuronic acid)) * 100, wherein the cohesive force is measured with an Oscillatory and Rotational Rheometer at an initial gap position of 1.0 mm and final gap position of 15 mm, with a speed of 0.93 mm/s, at 25 °C and measuring geometry of 25 mm plate/plate, wherein the crosslinked hyaluronic acid is obtained by crosslinking a hyaluronic acid having a molecular weight of 2,500,000 Da to 3,500,000 Da, or a salt thereof, and wherein the Modification degree is 3 to 4 mol%, wherein the A value is 200 to 650 Pa*N/(w/w)% and wherein the cohesive force is 1.0 to 1.7 N as measured by a Tack test, and wherein the Storage Elastic Modulus is 400 to 800 Pa (instant claim 1).
Instant claim 1 is clearly not limited to the BDDE crosslinker, as in instant claim 9, however, Applicant opines the crosslinking of the hyaluronic acid by a small amount of BDDE as a supportive of unexpected results. Additionally, the claims are directed to filler which applicant argues has unexpected properties based in the intended use as a dermal filler, where the examples all include about 2.0 wt.% (Table 1, of the instant Specification, and Table A in Applicant’s presently filed declaration). MPEP §716.02(d) states that: “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 instantly rejected claims are not commensurate with the results because they are not limited to BDDE crosslinker and the amount of “crosslinked hyaluronic acid” is generic to any amount where the results include about 2.0 wt.% of the same.
Response to Applicant’s Declaration under 37 CFR 1.132:
Applicant's Declaration under 37 CFR 1.132 filed 06/18/2025 has been fully considered but is not persuasive because the claims are broader in scope relative to the data in terms of the crosslinking agent used (BDDE – instant claim 9), and the amount of HA (HA content (w/w)%”.
Applicant states that: “l prepared supplemental data demonstrating the unexpected results of the claimed invention over the closest prior art, Dl, which further demonstrates the non-obviousness of the claimed invention.” (p. 3, item 6), and that: “unexpectedly, that when a ratio of lift capability of an unit content (w/w %) of hyaluronic acid contained in the filler relative to a modification degree (MoD) indicates a specific range, both elasticity and cohesivity are improved and thus, rheological properties of a high cohesivity of the monophasic filler and a high elasticity of the biphasic filler are achieved at the same time.” (p. 10, 1st paragraph). And that: “This confirms that the claimed invention provides a filler that simultaneously achieves a high cross-linking ratio, high elasticity, and high cohesivity with only a smaller amount of crosslinker than D1, which would have been unexpected over the closest prior D1.” (p. 20). Applicant further states that: “Applicant respectfully submits that the specification and supplemental data described above demonstrate that the claimed invention would have been unexpected over the closest prior art, Dl, which successfully rebuts any alleged prima face case of obviousness.” (p. 23, item 34).
“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.” (MPEP §716.02), “The evidence relied upon should establish ‘that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.’” and the burden is on Applicant to explain proffered date (MPEP §716.02(b)). Additionally, any unexpected results should be commensurate in scope with the results (MPEP §716.02(d)). Examples 1 and 2 are limited to hydrogels made using sodium hyaluronate (2.5 to 3.5 MDa), and each includes 4% (mol.) of BDDE. The claims are broader in scope relative to the data in terms of the crosslinking agent used (BDDE – instant claim 9), and the amount of HA (HA content (w/w)%”.
Applicant is reminded that, although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4, 8-14, 23 and 24 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 17/258,400 (claims 1-8, 12 and 13; hereafter ‘400) in view of D1 (KR_10-2015-0029578 A; published March 2015; K-PION Korean-language/English-language machine translation of KR 10-2015-0029578 relied on herein) in view of Yang et al. (“Determination of modification degree in BDDE-modified hyaluronic acid hydrogel by SEC/MS,” 2015, ELSEVIER; Carbohydrate Polymers, Vol. 131, pp. 233-239); JUNG (US 2018/0344896; published 06-DEC-2018); Edsman et al. (“Gel Properties of Hyaluronic Acid Dermal Fillers,” 2012; Wiley; Dermatologic Surgery, Vol. 38, Issue 7pt2, pp. 1170-1179) and LIU (US 2013/0123201; published May, 2013).
Instant claim 1 is discussed above.
Copending ‘400 claim 1 recites a hyaluronic acid hydrogel filler, comprising a hyaluronic acid, or its salt, and having a lift capability of 12,000 to 16,145 Pa*gf as measured by a rheometer and an injection force of 19 to 25 N as measured by a tensile tester, wherein the hyaluronic acid hydrogel filler comprises crosslinked hyaluronic acid particles having an average diameter of 300 to 400 μm, wherein the hyaluronic acid or its salt is crosslinked, wherein the crosslinked hyaluronic acid or its salt is crosslinked by using hyaluronic acid or salt having molecular weight of 2,500,000 Da or more, wherein a degree of cross-linking modification of the hyaluronic acid hydrogel filler is 1% to 7%, wherein the crosslinking ratio of the hyaluronic acid filler is 0.1 to 0.2, […] and wherein the filler has properties of both monophasic and biphasic fillers. Copending ‘400 claims 5-8 are substantially identical to instant claims 8-9, 11 and 12.
The difference between the instantly rejected claims and the copending claims is that the copending claims do not expressly claim the properties of instant claim 1, however, the claims of each copending case recite crosslinked hyaluronic acid with the same application as a dermal filler with same crosslinking agent (BDDE).
D1 discloses a method for preparing a hyaluronic acid cross-linked into a high-density reticulated structure and a wrinkle reducing filler comprising same, as discussed above and incorporated herein by reference.
Yang et al. teaches the t-MOD (degree of modification of hyaluronic acid) in the range of about 2.4 to 4.9 % (see whole document, particularly Table 1 and accompanying text; Table 7, col. “t-MOD(%)”, and accompanying text) which is consistent with the instant Specification on page 9, lines 14-18.
JUNG teaches hyaluronic acid having excellent viscoelasticity and being easily injectable, as discussed above and incorporated herein by reference.
Edsman et al. teaches the gel properties of hyaluronic acid dermal fillers, including the factors affecting the elastic modulus, as discussed above and incorporated herein by reference.
LIU teaches dermal filler compositions including antioxidants, including the factors affecting cohesivity, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of copending ‘400 because the copending claims are directed at the same crosslinked hyaluronic acid dermal fillers for cosmetic applications such as improving wrinkles. The skilled artisan would have been motivated to modify the claims of copending ‘400 and produce the instantly rejected claim because in order to optimize the properties of the cosmetic dermal filler. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because the prior art teaches methods of making including the factors affecting G’ (gel strength) and cohesivity.
This is a provisional obviousness-type double patenting rejection.
Claims 1, 4, 8-14, 23 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims U.S. Patent No. 12,128,154 (claims 1-11; hereafter ‘154) and U.S. Patent No. 12,576,185 (claims 1-10, hereafter ‘185) in view of D1 (KR_10-2015-0029578 A; published March 2015; K-PION Korean-language/English-language machine translation of KR 10-2015-0029578 relied on herein) in view of Yang et al. (“Determination of modification degree in BDDE-modified hyaluronic acid hydrogel by SEC/MS,” 2015, ELSEVIER; Carbohydrate Polymers, Vol. 131, pp. 233-239); JUNG (US 2018/0344896; published 06-DEC-2018); Edsman et al. (“Gel Properties of Hyaluronic Acid Dermal Fillers,” 2012; Wiley; Dermatologic Surgery, Vol. 38, Issue 7pt2, pp. 1170-1179) and LIU (US 2013/0123201; published May, 2013).
Instant claim 1 is discussed above.
‘154 claim 1 recites a filler comprising a hyaluronic acid hydrogel, wherein the hyaluronic acid hydrogel comprises a crosslinked hyaluronic acid obtained by crosslinking a hyaluronic acid having an average molecular weight of 2,000,000 Da to 4,000,000 Da, or a salt thereof with a crosslinking agent, wherein the crosslinked hyaluronic acid is contained in an amount of about 1 % to about 3% by weight based on the total weight of the filler, wherein the hyaluronic acid hydrogel comprises the crosslinked hyaluronic acid particles with an average diameter of 300 to 500 mm, and wherein a wrinkle improvement efficiency (WIE) parameter in accordance with Equation 1 as a value for filling properties is 0.6 or more and 20 or less […]. ‘154 claim 3 recites wherein a value of an elasticity value times a cohesivity value is at least 600 or more and 900 or less Pa*N […] which is substantially identical to instant claim 4. ‘154 claims 4, 7-9 are substantially identical to instant claims 14, 8, 11-12, respectively.
‘185 claim 1 recites a hyaluronic acid hydrogel filler, comprising a crosslinked hyaluronic acid, wherein the filler has a complex viscosity of 60,000 to 130,000 cP at an angular velocity of 1 Hz as measured by a rheometer, a storage elastic modulus G' of 400 to 800 Pa, and a cohesivity of 30 to 60 gf, and wherein the crosslinked hyaluronic acid is one in which a hyaluronic acid having a molecular weight of 2,500,000 Da or more is crosslinked and in the form of particles having an average diameter of 300 to 400 μm, a degree of modification (MOD) (%) of the hyaluronic acid as represented by Equation 1 following is in the range of 1 to 7%: […], and a crosslinking ratio (CrR) as represented by Equation 2 is in the range of 0.1 to 0.2: […]. ‘185 claim 3 recites the crosslinking agent is BDDE.
The difference between the instantly rejected claims and the claims of ‘154 is that the claims of ‘154 do not expressly claim the properties of instant claim 1, however, the claims of ‘154 case recite crosslinked hyaluronic acid with the same application as a dermal filler with same crosslinking agent (BDDE).
The difference between the instantly rejected claims and the claims of ‘185 is that the claims of ‘185 do not expressly claim the properties of instant claim 1, however, the claims of each case recite crosslinked hyaluronic acid with the same application as a dermal filler with same crosslinking agent (BDDE).
D1 discloses a method for preparing a hyaluronic acid cross-linked into a high-density reticulated structure and a wrinkle reducing filler comprising same, as discussed above and incorporated herein by reference.
Yang et al. teaches the t-MOD (degree of modification of hyaluronic acid) in the range of about 2.4 to 4.9 % (see whole document, particularly Table 1 and accompanying text; Table 7, col. “t-MOD(%)”, and accompanying text) which is consistent with the instant Specification on page 9, lines 14-18.
JUNG teaches hyaluronic acid having excellent viscoelasticity and being easily injectable, as discussed above and incorporated herein by reference.
Edsman et al. teaches the gel properties of hyaluronic acid dermal fillers, including the factors affecting the elastic modulus, as discussed above and incorporated herein by reference.
LIU teaches dermal filler compositions including antioxidants, including the factors affecting cohesivity, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of ‘154/’185 because the copending claims are directed at the same crosslinked hyaluronic acid dermal fillers for cosmetic applications such as improving wrinkles. The skilled artisan would have been motivated to modify the claims of ‘154/’185 and produce the instantly rejected claim because in order to optimize the properties of the cosmetic dermal filler. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because the prior art teaches methods of making including the factors affecting G’ (gel strength) and cohesivity.
Response to Arguments:
Applicant's arguments filed 06/18/2025 have been fully considered but they are not persuasive.
Applicant argues that: “Applicant's above arguments over Dl, in view of Yang, Jung, Edsman, and Liu are incorporated here. For at least the reasons discussed above, D1, in view of Yang, Jung, Edsman, and Liu, fails to remedy the deficiencies of the claims of l7/258,274, 17/258,400,[…] respectively, to teach or suggest the claimed invention as a whole.” (p. 15, last paragraph). And “Applicant's above arguments over D1, ln view of Yang, Jung, Edsman, and Liu are incorporated here. For at least the reasons discussed above, D 1, in view of Yang, Jung, Edsman,
and Liu fails to remedy the deficiencies of the claims of U.S. Patent No. 12,128,154 to teach or suggest the claimed invention as a whole.” (p. 16, 3rd paragraph).
In response the examiner has addressed Applicants arguments to the 103 above, which response is incorporated herein by reference.
Applicant is reminded that the merits of a provisional obviousness-type double patenting rejection can be addressed by both the applicant and the examiner without waiting for the first patent to issue. In re Mott, 539 F.2d 1291, 190 USPQ 536 (CCPA 1976); In re Wetterau, 356 F.2d 556, 148 USPQ 499 (CCPA 1966). Applicants are advised that Patent applicants now have the option to submit eTerminal Disclaimers (eTD) via EFS-Web, the USPTO’s electronic patent application filing system. Submitted eTDs are auto-processed and approved immediately by the USPTO if the request meets all submission requirements. Applicants can file an eTD in utility applications filed under 35 U.S.C. 111(a) or in compliance with 35 U.S.C. 371, and design applications. Applicants may still file a TD for manual review. See <www.uspto.gov/patents/process/file/efs/announce/index.jsp> for more information.
Conclusion
Claims 1, 4, 8-14, 23 and 24 are pending and have been examined on the merits. Claims 1, 4, 8-14, 23 and 24 are rejected under 35 U.S.C. 103; and claims are (provisionally) rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 17/258,400, and U.S. Patent Nos. 12,128,154 and 12,576,185. No claims allowed at this time.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
Prosecution Insights