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 .
Summary
Receipt of Applicants’ Arguments and Remarks filed on 06/11/2026 is acknowledged.
Claims 1-8 and 11-15 are pending.
Claims 9-10 remain cancelled.
Claims 1-8 and 11-15 are pending and under examination in this application.
Maintained Rejections
Claim Rejections - 35 USC § 103
The rejections previously made final are maintained, with the modifications set forth below.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Gobbo (WO 2007131546 A1) in view of Novel Hybrid Gels Made of High and Low Molecular Weight Hyaluronic Acid Induce Proliferation and Reduce Inflammation in an Osteoarthritis In Vitro Model Based on Human Synoviocytes and Chondrocytes (hereinafter the research article is referred as Stellavato), Elastoviscous hyaluronan in the synovium in health and disease (hereinafter the article is referred as Balazs) and further in view of Biotechnological Chondroitin a Novel Glycosamminoglycan with Remarkable Biological Function on Human Primary Chondrocytes (hereinafter the article is referred as Journal of Cellular Biochemistry (JCB)).
Gobbo teaches binary mixtures of hyaluronic acid (HA) samples having different characteristics with reference to viscosity and/or viscoelastic with different molecular weights and these HA mixtures demonstrated a right balance between the viscous modulus and viscoelastic modulus for their use, in particular, treating joint diseases (page 5, lines 7-11), to include inflammatory and/or traumatic joint disorders by intra-articular injection (abstract, page 5, lines 14-29). Moreover, Gobbo explicitly discloses their hyaluronic acid compositions as useful for intra-articular use via injection, establishing the preamble.
Regarding claim 1, [element A] “At least one low molecular weight linear hyaluronic acid or hyaluronate having an average molecular weight Mw ranging from 10 to 300 kDa. Gobbo teaches low molecular weight hyaluronic acid (LMWHA) in the range of 300,000 to 1,000,000 Da (300 to 1,000 kDa) (page 8, lines 20–26). The lower portion of Gobbo's LMWHA range (300 kDa) overlaps with the claimed upper boundary of 300 kDa, and a skilled person would have been motivated to explore lower molecular weight fractions within the broad claimed range.
Regarding [element B] “At least one high molecular weight linear hyaluronic acid or hyaluronate having average molecular weight Mw ranging from 1000 to 6000 kDa”. Gobbo explicitly teaches high molecular weight hyaluronic acid (HMWHA) in the range of 1,500,000 to 6,000,000 Da (1,500 to 6,000 kDa), which overlaps with and is encompassed within the claimed range of 1,000 to 6,000 kDa (page 8, lines 27–29).
Regarding [element C] “Weight ratio of low-molecular-weight hyaluronate to high-molecular-weight hyaluronate(s) ranging from 1:10 to 10:1”. Gobbo explicitly teaches mixtures of LMWHA:HMWHA, disclosing ratios including 80:20 (w/w) and 60:40 (w/w) (page 6, lines 1–4; page 5, lines 5–10), and also 50:50 w/w ratios (page 5, lines 16–23). The disclosed ratios of 80:20, 60:40, and 50:50 all fall within the claimed range of 1:10 (10%) to 10:1 (90%). A person of ordinary skill in the art (PHOSITA) would have been motivated to optimize the ratio of LMWHA:HMWHA within the range taught by Gobbo in order to obtain desired rheological properties, as Gobbo itself teaches that different ratios produce different viscoelastic balances (page 6, lines 1–10).
Regarding [element D] “Dynamic viscosity at 25°C ranging from 10 to 60 Pa*s (at 0.01 s⁻¹)”. Gobbo teaches a flow viscosity of at least 5 Pa/sec at a shear rate of 1 s⁻¹ and a most preferred dynamic viscosity in the range of 10 to 15 Pa*s at a shear rate of 1 s⁻¹ at 25°C (page 8, lines 8–14).
Regarding [element E] “Crossover frequency ranging from 1 to 10 rad/s”. Gobbo teaches that tuning the LMWHA:HMWHA ratio shifts the G'=G'' transition to lower frequencies (page 6, lines 1–4). A PHOSITA would therefore have been motivated to modify the ratio to shift the crossover frequency into the claimed range of 1 to 10 rad/s, with a reasonable expectation of success based on the teachings of Gobbo.
Regarding [element F] “Viscous and elastic modulus value at the crossover frequency ranging from 20 to 110 Pa”. Gobbo further teaches G' values in a range comprised from 7.5 to 90 Pa and G'' values from 7 to 20 Pa at 1 Hz (page 8, lines 8–10).
Regarding claim 2, as noted above, Gobbo teaches at least two different high molecular weight linear hyaluronic acid or hyaluronates.
Regarding claim 15, as noted in [Element C] Gobbo teaches ratios of 80:20, 60:40, and 50:50 w/w (LMWHA:HMWHA), corresponding to ratios of 4:1, 1.5:1, and 1:1 respectively. All of these ratios fall within the claimed sub-range of 1:5 to 5:1.
Gobbo fails to specifically teach additional glycosaminoglycan, lubricin and non-sulphated chondroitin.
Stellavato teaches properties of hybrid cooperative complexes (HCC) based on high and low molecular weight hyaluronan (HCC) compared to high molecular weight hyaluronan (H-HA) on human primary cells derived by pathological joints (page 1, abstract) and the modifications of hyaluronic acid (HA) through cross-linking agents or biophysical interactions to obtain hybrid complexes, specifically, hybrid complexes are based on high and low molecular weight of pharm-grade HA, and their properties have been tested in several in vitro cellular models (page 2, last 6 lines of 1st ¶). Moreover, Stellavato teaches hyaluronic acid (hyaluronic acid-based gels) having high molecular weight (H-HA; MW 1400± 200 kDa) and low molecular weight (L-HA; MW 100± 20 kDa), with a concentration of 16 mg H-HA and 16 mg L-HA in 1 mL volume (ratio of 1:1) (page 8, ¶ 2.1 of Materials and Methods), and the dynamic viscosity of the sample was registered as function of shear rate (0.001 – 300 s-1) at 25°C (page 9, 1st ¶ of 2.2. Rheological Studies), and the results of the rheological characterization of hybrid cooperative complexes (HCC) are reported in Figure 2, wherein the flow curve of the preparation (Figure 2(a)) indicates a pseudoplastic behavior, with a value of zero-shear viscosity equal to 12.1 Pa s., wherein viscosity remains constant within 0.3 s-1 shear rate and then reduces with a shear thinning ratio (ƞ0.1/ ƞ250) of about 13, and the mechanical spectrum (Figure 2(b)) indicates an essential fluid behavior at low frequency values with G" exceeding G: Both moduli increased in frequency ·with a faster G' increase until a crossover point registered at about 4Hz and at higher frequencies, the preparation exhibited an essential elastic behavior with G' exceeding G”, wherein the G' values for HCC at 0.5 and 2.5 Hz frequency are 13.7 and 58.6 Pa, respectively (page 10-11, ¶ 3.1 of Results). Therefore, the limitation of low and high molecular weight of HA overlaps instant range of 10 to 300 kDa; 1000 to 6000 kDa), dynamic viscosity overlaps instant temperature at 25 °C and range of 10 to 60 Pa*s (at 0.1 s-1), with crossover frequency overlaps of instant range 1 to 10 rad/s (HCC at 0.5 and 2.5 Hz), and viscous and elastic modulus (G”-G’) crossover frequency overlaps instant range of 20 to 110 Pa.
Regarding claim 1, [element A] “At least one low molecular weight linear hyaluronic acid or hyaluronate having an average molecular weight Mw ranging from 10 to 300 kDa. Stellavato teaches low molecular weight HA (L-HA; MW 100 ± 20 kDa), which falls squarely within the claimed range of 10 to 300 kDa (page 8, ¶ 2.1 of Materials and Methods). The combination of Gobbo and Stellavato thus teaches an LMW HA within 10 to 300 kDa. Claim 3 (Mw 20–150 kDa), claim 13 (Mw 50–100 kDa), and claim 14 (Mw 70–90 kDa) are similarly taught by Stellavato's L-HA (100 ± 20 kDa).
Regarding [element B] “At least one high molecular weight linear hyaluronic acid or hyaluronate having average molecular weight Mw ranging from 1000 to 6000 kDa”. Stellavato further teaches H-HA having MW 1400 ± 200 kDa (i.e., 1,200–1,600 kDa), which falls within the claimed range of 1,000 to 6,000 kDa (page 8, ¶ 2.1). Claims 4 and 5 (H-HA Mw 1,000 to 4,500 kDa; 1,000 to 3,500 kDa) are directly taught by Gobbo's HMWHA (1,500–6,000 kDa) and Stellavato's H-HA (1,400 kDa), both of which fall within or overlap these sub-ranges.
Regarding [element E] “Crossover frequency ranging from 1 to 10 rad/s”. Stellavato reports a crossover frequency for its hybrid cooperative complex (HCC) of approximately 4 Hz (approximately 25 rad/s) (page 10–11, ¶ 3.1 of Results). While this value is above the upper end of the claimed range (10 rad/s), Stellavato demonstrates that the crossover frequency is tunable based on composition and specifically, that HCC has a crossover frequency higher than synovial fluid, but that by modifying the HA composition a skilled person could obtain a lower crossover frequency. A PHOSITA would therefore have been motivated to modify the ratio to shift the crossover frequency into the claimed range of 1 to 10 rad/s, with a reasonable expectation of success based on the teachings of both Gobbo and Stellavato.
Regarding [element F] “Viscous and elastic modulus value at the crossover frequency ranging from 20 to 110 Pa”. Stellavato reports G' values for HCC at 0.5 Hz and 2.5 Hz (approximately 3.1 and 15.7 rad/s) of 13.7 Pa and 58.6 Pa, respectively (page 10–11, ¶ 3.1). These crossover modulus values at frequencies near the claimed range of 1 to 10 rad/s are within and overlap the claimed modulus range of 20 to 110 Pa. Gobbo further teaches G' values in a range comprised from 7.5 to 90 Pa and G'' values from 7 to 20 Pa at 1 Hz (page 8, lines 8–10). A PHOSITA would have understood that optimizing the HA ratio in the combined composition of Gobbo/Stellavato to achieve a crossover frequency of 1–10 rad/s would simultaneously yield crossover modulus values within the claimed range of 20–110 Pa, which encompasses the values taught by both references.
Regarding claims 3, 13 and 14, Stellavato teaches low molecular weight (L-HA; MW 100± 20 kDa) (page 8, ¶ 2.1 of Materials and Methods). Therefore, the L-HA MW overlaps with instant ranges of 20 to 150 kDa; 50 to 100 kDa; and 70 to 90 kDa.
Regarding claims 4, 5 and 15, Stellavato teaches low molecular weight (L-HA; MW 100± 20 kDa) and high molecular weight (H-HA; MW 1400± 200kDa) (page 8, ¶ 2.1 of Materials and Methods). Therefore, the H-HA MW overlaps with instant ranges of 1000 to 4500 kDa; L-HA MW of 70 to 90 kDa and H-HA MW of 1000 to 3500 kDa.
Stellavato fails to specifically teach at least two different high molecular weight linear hyaluronic acids or hyaluronates.
Balazs teaches the therapeutic modality of viscosupplementation, the intra-articular application of elastoviscous hyaluronan and its derivatives (hylan A and hylan B) (page 189, ¶ Introduction). Notably, Balazs disclose in healthy tissues the average molecular weight of hyaluronan is approximately 6 million, and as are all other hyaluronans in the intercellular matrix, synovial hyaluronan is also polydisperse, and molecules of up to 8 million molecular weight and as small as 2 million are present in the healthy human and other animal synovial fluids, thus this polydispersity is very important because in pathological conditions, the polydispersity increases as a result of the occurrence of molecules in the range of 250,000 to 2 million molecular weight, and the occurrence of this low molecular weight fraction has been interpreted to be a result of partial intra-articular degradation (oxidative or free radical) or as a newly synthesized fraction of hyaluronan (page 189, ¶ Hyaluronan). Moreover, the average molecular weight of hyaluronan is varied between 2 and 5 million, representing a broad distribution of molecules between 250,000 and 7 million molecular weight (page 190, 1st ¶). Thus, Balazs similarly discloses the therapeutic modality of viscosupplementation by intra-articular application of elastoviscous hyaluronan (page 189, ¶ Introduction).
Regarding claims 6, 7 and 8, Balazs teaches phospholipid and lubricin, wherein lubricin is found to contribute to the slipperiness of the cartilage surface, and also present in synovial fluid and was found to be homologous to the superficial zone protein, wherein surface-active phospholipids have also been identified in the lamina splendens, and it has been suggested that their hydrophobicity contributes to the reduction of friction on the cartilage surface (page 192, 3rd 1st ¶). A person having ordinary skill in the art (PHOSITA) would have known that phosphatidylcholine is a type of phospholipid and therefore, the limitation of phospholipid, phosphatidyl choline and lubricin it taught.
Regarding claim 11, Balazs explicitly teaches a method for substituting synovial fluid (page 201, last ¶). The administration of elastoviscous hyaluronan intra-articularly as a synovial fluid substitute is a core teaching of Balazs. A PHOSITA would have been motivated to apply the intra-articular composition of claim 1 (as taught by the Gobbo/Stellavato/JCB combination) in Balazs's disclosed synovial fluid substitution method.
Regarding claim 12, Balazs explicitly teaches the injection of elastoviscous hyaluronan or hylan solutions into painful knee joints (viscosupplementation) has been shown to be effective in reducing pain and improving function in a broad spectrum of osteoarthritic patients (page 201, 1st ¶). Therefore, the limitation of a method of treating joint disorders by administering a pharmaceutical effective amount to patients is taught,
Balazs fails to specifically teach glycosaminoglycan and non-sulphated chondroitin.
Journal of Cellular Biochemistry (JCB) teaches comparison and effects of new biotechnological chondroitin (BC) and a commercial extractive chondroitin sulfate (CS) on human chondrocytes in vitro culture, evaluate the anti-inflammatory effects of the innovative (BC) compared to extractive (CS), and results have shown that (BC) enhances cell proliferation, preserving chondrocyte phenotype increasing type II collagen expression up to 10 days of treatment and reduces inflammatory response in IL-β treated chondrocytes respect to CS treated cells, which suggest that this new (BC) is of foremost importance in translational medicine because it can be applied in novel scaffolds and pharmaceutical preparations aiming at cartilage pathology treatments such as the osteoarthritis (Abstract).
Regarding claim 1 [element G-Amended] “Wherein said composition further comprises an additional glycosaminoglycan, and wherein the additional glycosaminoglycan is non-sulphated chondroitin”. JCB specifically teaches non-sulphated (unsulfated) biotechnological chondroitin (BC), a biopolymer obtained through novel and patented biotechnological production processes (page 2159, 1st ¶). JCB teaches that non-sulphated BC exhibits superior anti-inflammatory activity compared to conventional extractive chondroitin sulfate, enhances cell proliferation, preserves chondrocyte phenotype, increases type II collagen expression, and reduces inflammatory response in IL-β treated chondrocytes (Abstract). JCB further identifies the extracellular matrix as composed of fibrous proteins and glycosaminoglycans (GAGs) (page 2159, 1st ¶), establishing chondroitin as a glycosaminoglycan as claimed. A PHOSITA would have been motivated to incorporate non-sulphated chondroitin into the HA mixture of Gobbo/Stellavato because JCB demonstrates that non-sulphated chondroitin provides superior biological and anti-inflammatory benefits in joint tissue models — benefits that a skilled artisan seeking to develop an intra-articular composition mimicking synovial fluid would have been strongly motivated to achieve. Gobbo fails to specifically teach glycosaminoglycan additives, and Balazs is silent on non-sulphated chondroitin specifically, but the combination of Gobbo, Stellavato, and JCB provides explicit teaching and motivation for all elements of amended claim 1.
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 use the hybrid cooperative complexes (HCC) based on high and low molecular weight hyaluronan as taught by Gobbo and incorporate the two different high molecular weight linear hyaluronic acids or hyaluronates in the composition as taught by Stellavato and further improve the intra-articular composition by incorporating lubricin and the non-sulphated chondroitin as taught by Balazs in view of Journal of Cellular Biochemistry (JCB). One would have been motivated to do so because the combined teaching of Stellavato, Gobbo, Balazs and Journal of Cellular Biochemistry discloses intra-articular composition comprising LMWHA and HMWHA mixtures, lubricin and the non-sulphated chondroitin benefits in such a composition. One of ordinary skill in the art would have been motivated to add lubricin because lubricin has been found to contribute to the slipperiness of the cartilage surface and is also present in the synovial fluid as taught by Balazs, therefore the addition of lubricin has been shown to have synergistic benefits. Furthermore, One of ordinary skill in the art would have been motivated to add the unsulfated biotechnological chondroitin (BC) biopolymer to the hyaluronic acid composition because the addition of (BC) results suggest increase cell proliferation, enhances chondrocyte phenotype lifespan, have shown beneficial biological activity with respect to inflammation, and specifically, BC is superior to chondroitin sulfate (CS) in the reduction of cytokines levels in chondrocyte inflammation model in vitro as taught by Journal of Cellular Biochemistry. One of ordinary skill in the art would have been motivated to do this because all the references are drawn to methods for substituting synovial fluid and for treating joint disorders in patients in need thereof.
One of ordinary skill in the art would have found it obvious to apply the different low and high molecular weights of hyaluronic acids in combination, optimize the ratios in order to obtain the desired rheological properties and the desired balance between viscosity and viscoelasticity of hyaluronic acid that would be useful for treatments of intra-articular disorder or other treatments of interests.
Response to Arguments
Applicant’s arguments filed 06/11/2026 have been fully considered but they are not persuasive.
Argument 1: Stellavato is retracted and cannot establish a prima facie case
Applicant argues that Stellavato has been retracted by its editorial board due to concerns with the reliability of the data and therefore cannot form the basis of a prima facie obviousness rejection.
This argument is not persuasive.
Applicant contends for the second time that Stellavato, having been retracted in its entirety by the editorial board of BioMed Research International, cannot be relied upon even for its structural and compositional disclosures. Applicant further argues that a retracted reference undermines any reasonable expectation of success because, in Applicant’s view, no portion of the publication retains credibility once a retraction notice has issued. Examiner respectfully disagrees on both grounds.
First, retraction of a scientific publication does not automatically render it disqualified as prior art under 35 U.S.C. § 102/103. See MPEP § 2132; see also Ex parte Beattie, 974 F.2d 1309 (Fed. Cir. 1992). The retraction notice itself — which Applicant has made of record — identifies the specific basis for retraction with precision: figure duplications in Figure 6(a), specifically, overlapping cell-image panels in the 24h/48h HCC panels and the 72h/96h H-HA panels. The retraction thus concerns biological efficacy imaging data in the in vitro cellular proliferation and inflammation assays. It does not identify any concern with, and does not purport to retract, the Materials and Methods section (§ 2.1), the rheological characterization data (§ 2.2 and Figure 2), or the compositional disclosures of the HA molecular weights and ratios used. The Examiner relies on Stellavato solely for those non-retracted structural and compositional disclosures: (1) H-HA of MW 1400 ± 200 kDa and L-HA of MW 100 ± 20 kDa (§ 2.1, Materials and Methods); (2) a 1:1 concentration ratio of 16 mg H-HA and 16 mg L-HA per 1 mL; and (3) rheological characterization methodology including zero-shear viscosity of 12.1 Pa·s and crossover frequency at approximately 4 Hz (Figure 2 and § 3.1). None of these disclosures is implicated by the identified figure duplications, and Applicant has provided no evidence that the retraction extends to or undermines the reliability of these specific data.
Second, and dispositive, Gobbo (WO 2007/131546 A1) stands as an independently sufficient primary reference for the core structural and rheological limitations of claim 1. Even if Stellavato were entirely disregarded — which the Examiner maintains is not warranted — the rejection is fully sustained over Gobbo in view of Balazs and JCB alone. Applicant’s argument regarding Stellavato is therefore moot with respect to the validity of the rejection as a whole.
Argument 2: Gobbo's rheological values are measured at different shear rates and are not comparable to the claimed values. Applicant argues that the dynamic viscosity and elastic modulus values taught by Gobbo are measured at 0.1 s⁻¹ (or 1 s⁻¹ for flow viscosity), not at the claimed condition of 0.01 s⁻¹, and therefore do not overlap with or anticipate the claimed dynamic viscosity of 10 to 60 Pa*s at 0.01 s⁻¹.
This argument is not persuasive. Applicant’s position requires ignoring well-established principles of polymer rheology that are within the ordinary skill of a PHOSITA in the pharmaceutical formulation art.
Hyaluronic acid solutions and HA mixtures are among the most extensively characterized shear-thinning (pseudoplastic) biopolymers in the pharmaceutical literature. It is fundamental and uncontroverted rheological knowledge that pseudoplastic fluids exhibit a Newtonian plateau at low shear rates (the zero-shear viscosity region) and progressively decreasing viscosity as shear rate increases. This is the defining characteristic of shear-thinning behavior. Consequently, a PHOSITA would understand without any experimentation that a composition exhibiting 10–15 Pa·s at 1 s⁻¹ (as taught by Gobbo) will necessarily exhibit equal or higher viscosity at 0.01 s⁻¹ — two orders of magnitude lower in shear rate, well within the zero-shear plateau regime for HA solutions of this molecular weight. This is not speculation; it is a direct and predictable consequence of pseudoplastic fluid behavior.
Importantly, Stellavato directly confirms this principle for the specific type of HA hybrid composition at issue. Stellavato reports a zero-shear viscosity of 12.1 Pa·s for its HCC formulation, with viscosity remaining constant (i.e., at the Newtonian plateau) within 0.3 s⁻¹. The claimed measurement condition of 0.01 s⁻¹ falls squarely within this zero-shear plateau, meaning the viscosity at 0.01 s⁻¹ is the zero-shear viscosity itself. A composition exhibiting 10–15 Pa·s in the shear-thinning regime at 1 s⁻¹ will have a zero-shear viscosity that is higher still — placing it squarely within the claimed range of 10–60 Pa·s at 0.01 s⁻¹.
Applicant has not submitted any experimental data demonstrating that Gobbo’s compositions fail to meet the claimed viscosity range when measured at 0.01 s⁻¹. Argument alone, unsupported by objective evidence, is insufficient to rebut a prima facie case of obviousness where the examiner’s position is grounded in established scientific principles and confirmed by the disclosure of a reference of record. See In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). The argument is accordingly not persuasive.
Argument 3: None of the references teaches combining the HA mixture with non-sulphated chondroitin at the claimed specific ratios and rheological properties
Applicant argues that neither the cited references individually nor in combination describes, teaches, or suggests that combining non-sulphated chondroitin with a binary or ternary mixture of native linear HA at the specific claimed ratios and rheological properties would result in the observed rheological benefits of the claimed invention.
This argument is not persuasive. Applicant conflates the disclosure requirement for obviousness with the requirement for anticipation. Under 35 U.S.C. § 103, it is not required that the prior art explicitly describe combining all claimed elements in the same formulation context, or that a reference teach the ingredient for use in an injectable intra-articular composition specifically, in order to provide motivation to combine. It is sufficient that: (1) all elements of the claimed composition are individually taught by the prior art; and (2) a PHOSITA would have had a reason to combine the teachings with a reasonable expectation of success. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
Applicant argues that JCB describes non-sulphated chondroitin only in an in vitro chondrocyte culture context, and therefore provides no motivation to incorporate it into an injectable HA composition with specific rheological properties. This argument misapplies the law. Motivation to combine does not require that the secondary reference use the relevant ingredient in an identical formulation or delivery context. JCB explicitly establishes that non-sulphated biotechnological chondroitin (BC) is a glycosaminoglycan with superior anti-inflammatory and chondroprotective biological activity compared to conventional chondroitin sulfate in the context of joint tissue and osteoarthritis — the identical therapeutic indication targeted by all four references. A PHOSITA seeking to develop an intra-articular composition mimicking synovial fluid and providing optimal joint therapy would have had clear and explicit motivation to incorporate a component documented to exhibit superior biological activity in that very tissue context. See In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980) (motivation to combine may arise from the nature of the problem to be solved and the expected beneficial results of the combination).
Furthermore, Applicant has not demonstrated that the addition of non-sulphated chondroitin to the claimed HA composition produces any unexpected rheological result. The claimed rheological parameters (dynamic viscosity, crossover frequency, and modulus at crossover) are properties of the HA mixture itself, taught by Gobbo and Stellavato independently of the glycosaminoglycan additive. The addition of non-sulphated chondroitin as claimed is thus the combination of a known HA formulation (Gobbo/Stellavato) with a known ingredient (JCB) for known, predictable biological benefits — the paradigmatic scenario of obviousness under KSR. Applicant’s argument is not persuasive.
Argument 4: The combined references fail to describe all elements of the claimed invention. Applicant argues that the combination of the cited references cannot render obvious the presently claimed invention because they fail to describe, teach, or suggest all elements of the presently claimed invention.
This argument is not persuasive and is addressed by the foregoing responses to Arguments 1–3. As set forth in detail in the rejection above and in the responses to Applicant’s arguments, the combination of Gobbo (primary), Stellavato, Balazs, and JCB collectively teaches each and every limitation of claims 1–8 and 11–15. For clarity, the contribution of each reference is summarized as follows:
Gobbo teaches: the intra-articular use; LMW and HMW HA molecular weight fractions with partial overlap of claimed ranges; binary HA mixture ratios within the claimed 1:10 to 10:1 range; dynamic viscosity and viscoelastic modulus values; and the therapeutic use for treating joint disorders.
Stellavato teaches: LMW HA (L-HA; 100 ± 20 kDa) within the claimed 10–300 kDa range; HMW HA (H-HA; 1400 ± 200 kDa) within the 1,000–6,000 kDa range; rheological characterization of hybrid HA complexes including crossover frequency; and viscosity at 25°C.
Balazs teaches: the intra-articular therapeutic context; synovial fluid composition and its components; methods for substituting synovial fluid; and methods for treating joint disorders in patients.
JCB teaches: non-sulphated (unsulfated) biotechnological chondroitin as a glycosaminoglycan; its superior biological and anti-inflammatory activity compared to conventional chondroitin sulfate; and its relevance to joint tissue and osteoarthritis treatment.
All elements of the amended claims are thus accounted for in the cited prior art. A PHOSITA would have had clear motivation to combine these references — all directed to the same field of intra-articular joint therapy — with a reasonable expectation of success. Applicant’s generalized assertion that the references fail to collectively teach the claimed invention is not supported by specific argument addressing the claim-by-claim mapping set forth in the rejection, and is accordingly not persuasive.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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