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 .
DETAILED ACTION
Pursuant to the amendment dated 12/24/2025, claim1 is amended and claims 4 and 11-14 are canceled. Claims 1-3 and 5-10 are pending in the instant application and are examined on the merits herein.
Priority
This application is a National Stage Application of PCT/IB2020/055848, filed on 06/22/2020 which foreign priority to Italy 102019000009933 filed on 06/24/2019.
Withdrawn Rejections
Applicant’s amendment, filed on 12/24/2025, with respect to the rejection of claims 1-3 and 5-10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, has been fully considered and is persuasive. Applicant has amended claim 1 to add a saline solution. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 12/24/2025, with respect to the rejection of claim 6 under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), fourth paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, has been fully considered and is persuasive. Applicant has amended claim 1 to add the limitation of “optionally pharmaceutically acceptable excipients”. Claim 6 now includes all the limitations as the claim upon which it depends, claim 1. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 12/24/2025, with respect to the rejection of claims 1, 5, 6 and 8 under 35 U.S.C. 103 as being unpatentable over Schiavinato et al. (US 7863256 B2, published 01/04/2011, see PTO-892 dated 06/11/2025) and Patterson et al. (Biomaterials, published 06/23/2010, see PTO-892 dated 06/11/2025) has been fully considered and is persuasive. Applicant has amended claim 1 to require hyaluronic acid in a saline solution. The combined teachings of Schiavinato and Patterson do not teach the use of a hyaluronic acid in a saline solution. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 12/24/2025, with respect to the rejection of claims 2-3, 7, 9, and 10 under 35 U.S.C. 103 as being unpatentable over Schiavinato et al. (US 7863256 B2, published 01/04/2011, see PTO-892 dated 06/11/2025) and Patterson et al. (Biomaterials, published 06/23/2010, see PTO-892 dated 06/11/2025) as applied to claim 1 above, and further in view of Mayo Clinic (www.mayoclinic.org, accessed 12/24/2024, see PTO-892 dated 06/11/2025) has been fully considered and is persuasive. Applicant has amended claim 1 to require hyaluronic acid in a saline solution. The combined teachings of Schiavinato and Patterson do not teach the use of a hyaluronic acid in a saline solution. The rejection is hereby withdrawn.
Rejections Necessitated by Amendment
The following are new ground(s) necessitated by Applicants' amendment, filed on 11/04/2025, wherein instant independent claims 1 was amended to alter the breadth and scope of the claim, and wherein the remaining pending claims 2-17, 19, 21, 23, 25, 30, 32 and 39 depend from said independent claim.
New Grounds of Rejection
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.
Claims 1, 5, 6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Schiavinato et al. (US 7863256 82, published 01/04/2011, see PTO-892 dated 06/11/2025), Patterson et al. (Biomaterials, published 06/23/2010, see PTO-892 dated 06/11/2025), and Callegaro et al. (US 2012/0114609 A1, published 05/10/2012, see PTO-892).
Schiavinato is drawn to the administration of amide derivatives of hyaluronic acid (HA) and biomaterials made of amide derivatives of HA, particularly the hexadecylamide of HA (abstract). Schiavinato teaches that HYADD™ derivatives possess the intrinsic properties of HA, with a decidedly longer residence time and they have no toxic effect on chondrocytes treated in vitro and in vivo (column 4, lines 38-55). Schiavinato teaches that HYADD™ derivatives reduce the formation of osteophytes (column 3, line 26-28). Schiavinato teaches the use of a hexadecyl amide prepared from a hyaluronic acid (HA) with an average MW ranging from 500 kDa to 750 kDa (column 5, line 3) and an average degree of amidation of 0.1-5%, more preferably 2-5%, and exemplified at 2% (column 5, line 15-16; col. 9, line 39). When using the HYADD™ derivative the average degree of amidation was 2-3% (column 5, line 6). Schiavinato teaches that the amide HA derivatives can be formulated with excipients to obtain the best possible pharmaceutical formulation (column 9, lines 58-60). Schiavinato teaches that HYADD™ is soluble in water, phosphate buffer and saline solution (column 2, lines 10-11). Schiavinato exemplified the administration to a subject a HYADD compound with a concentration of 8 mg/mL (column 8, line 38). Since Schiavinato uses a HYADD compound having the same properties as the instant claims and the same concentration of 8 mg/ml (column 8, line 38) used in instant example 1, the viscosity of Schiavinato's invention would necessarily be the same as the instant application.
Schiavinato does not teach a method of treating bone mineralization in bone traumas or an injection route of local, locoregional, intra- or peri-osseous. Schiavinato does not teach that the HYADD™ is in a saline solution.
Patterson is drawn to the study of hyaluronic acid hydrogels for oriented bone regeneration (title). Patterson teaches that non-healing fractures can result from trauma, disease, or age-related bone loss. Patterson teaches that hyaluronic acid has been show to support bone growth in combination with other osteoconductive molecules and is able to increase some markers of differentiation in cultured osteoblasts. The HA can be modified and crosslinked into a hydrogel (page 6773, column 2). Patterson exemplified localized delivery of a HA hydrogel composition, a control composition of the HA hydrogel only and a composition containing the HA hydrogel with bone morphogenetic protein-2 (BMP-2), to rat model where a defect was made in the parietal bones (page 6774, column 1). While the HA hydrogel composition with BMP-2 had significantly higher mineralization levels than the HA hydrogel only composition, the HA hydrogel only composition also had mineralization (Figure 4, page 6776). Patterson teaches that these materials have potential for clinical application to bone defects (page 6780, column 1).
Callegaro is drawn to a biological material suitable for the therapy of osteoarthrosis, ligament damage and for the treatment of joint disorders (title). Callegaro teaches that the biological material comprises a viscous solution that is an aqueous solution of octylamide of hyaluronic acid with a molecular range between 450 and 730 kDa and a concentration range between 1 and 10 mg/mL and the hexadecylamide of hyaluronic acid with an average molecular weight molecular range between 450 and 730 kDa comprised between 0.2 and 1.5 mg/ml (paragraphs 0044-0046). Callegaro teaches that the hyaluronic acid solution may be diluted in a saline solution (paragraph 0032). The viscous solution has a dynamic viscosity measured at 20°C and a shear rate of D=350 s-1, comprised between 100 and 250 cPoise and/or a Kinematic viscosity comprised between 99 and 248 cSt when measured at the same conditions (paragraph 0027). Callegaro teaches that the compositions may be used orthopedy in the treatment of cartilage and bone defects including local use (paragraph 0054).
It would have been prima facie obvious to combine the teachings of Schiavinato, Patterson, and Callegaro before the effective filing date of the claimed invention by modifying the method of applying the HA composition by Schiavinato to treat bone defects as taught by Callegaro and bone mineralization as taught by Patterson to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the method of applying the HA composition taught by Schiavinato to treat bone defects and bone mineralization because Callegaro teaches that a composition comprising a hexadecyl amide hyaluronic acid in a saline solution may be used to treat bone defects and Patterson showed that HA hydrogels can be used to treat bone mineralization at bone fracture sites in a rat model. One of ordinary skill in the art would have a reasonable expectation of success because Callegaro teaches that a composition comprising a hexadecyl amide hyaluronic acid and Patterson teaches that hyaluronic acid has been show to support bone growth and Patterson exemplified a HA hydrogel that induced bone mineralization in a rat model.
It would have been prima facie obvious to combine the teachings of Schiavinato, Patterson, and Callegaro before the effective filing date of the claimed invention by modifying the HA composition taught by Schiavinato to be in a saline solution as taught by Patterson to arrive at the claimed invention. It would have been prima facie obvious for a person of ordinary skill in the art to modify the composition comprising HYADD™ taught by Schiavinato to be in saline as taught by Callegaro because Schiavinato teaches that HYADD™ is soluble in saline solution and Callegaro teaches a composition comprising a hexadecylamide of hyaluronic acid in saline. One of ordinary skill in the art would have a reasonable expectation of success because Schiavinato teaches that HYADD™ is soluble in saline and Callegaro teaches the hexadecylamide of hyaluronic acid in saline.
Claims 2-3, 7, 9, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Schiavinato et al. (US 7863256 82, published January 4, 2011, see PTO-892), Patterson et al. (Biomaterials, published 06/23/2010, see PTO-892 dated 06/11/2025), and Callegaro et al. (US 2012/0114609 A1, published 05/10/2012, see PTO-892) as applied to claim 1 above, and further in view of Mayo Clinic (www.mayoclinic.org, accessed December 24, 2024, see PTO-892).
Claim 1 is rejected as discussed above.
The combined teachings of Schiavinato, Patterson and Callegaro are discussed above.
The combined teachings of Schiavinato, Patterson and Callegaro do not teach the method wherein the patient is suffering from a pathology characterized by a T-score index lower than -1 or lower than -2.5 as recited in claims 2 and 3. The combined teachings of Schiavinato and Patterson do not teach the method wherein the patient is suffering from diabetes, Gaucher disease, osteomalacia, rickets, postmenopausal primary or elderly osteoporosis, osteoporosis secondary to chronic drug intake, hormonal imbalances and related diseases, or avitaminosis and/or protein-calorie malnutrition as recited in claims 7, 9 and 10.
The Mayo Clinic teaches that the T-score is used to determine bone density of a patient and that a patient with a bone density T-score lower than -1 is a sign of osteopenia and a score lower than -2.5 is an indication of osteoporosis (bone density test, page 4). Mayo clinic also teaches that osteoporosis can result from a patient who have suffered diseases such as cancer and undergone chemotherapy, patients that have lowered sex hormones (hypogonadism), patients that have overactive adrenal glands (Cushing's disease), and patients that have had long-term use of corticosteroid medicines.
It would have been prima facie obvious to combine the combined teachings of Schiavinato, Patterson and Callegaro with the teachings of Mayo Clinic before the effective filing date of the claimed invention by modifying the method for treating patients with the composition of HA capable of carrying a pharmaceutical composition for bone repair as taught by the combined teachings of Schiavinato, Patterson and Callegaro to patients meeting the criteria and types of patients that would most likely have bone trauma resulting from osteoporosis to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the method to be applied to patients that would benefit from bone mineralization such as those that meet the patient criteria of osteoporosis as taught by Mayo Clinic. One of ordinary skill in the art would have a reasonable expectation of success because Callegaro teaches that compositions comprising a hexadecylamide of hyaluronic acid can be used to treat bone defects.
Response to Arguments
Applicant's arguments filed 12/24/2025 have been fully considered in so much as they apply to the amended claims but they are not persuasive.
Applicant argues that the viscosity of the instant invention is higher than the two in vitro experiments at the concentration of 0.5 mg/mL HYADD™ exemplified by Schiavinato. Applicant also argues that in the in vivo experiment was an intra-articular injection and showed that the 8 mg/mL HYADD™ composition did not stay confined to the synovial space, but is detected on the surface of the articular cartilage within 2 days and supports the use of the composition for cartilage regeneration. The argument is not persuasive. Schiavinato was relied upon to teach the HYADD™ composition and exemplifies both 0.5 mg/mL and 8 mg/mL compositions in vitro and in vivo. Although Schiavinato was silent about the viscosity of the solution, the viscosity limitation of the instant claims would have been met by the exemplified 8 mg/mL HYADD™ composition. Regarding the argument that the in vivo experiment supports cartilage regeneration rather than the bone mineralization of the instant invention, Schiavinato was relied upon to support the application of an 8mg/mL HYADD™ solution to a subject, while Patterson teaches hyaluronic acid hydrogels for bone mineralization and Callegaro teaches a hexadecylamide of hyaluronic acid for treatment of bone defects. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that the instant specification demonstrates that HYADD-4 has a surprisingly better remineralizing effect than linear HA without any osteoinductive factor. The argument is not persuasive. The instant examples compare a 0.5 mg/mL and a 1 mg/mL HYADD-4 solution to hyaluronic acid alone for MCS mineralization and COL15A1 expression (instant Fig. 1 and Fig. 2), but does not provide any standard deviation data to show that the HYADD-4 results are statistically significant compared to either hyaluronic acid alone or the control. Further, Schiavinato teaches that HYADD™ is nontoxic to chondrocytes and reduces the formation of osteophytes.
Applicant argues that one of ordinary skill in the art would have had no proper reason, rationale, or motivation to think that an HA derivative (hexadecylamide) capable of inducing proliferation of cells meant to replace elastic tissue like cartilage (Schiavinato '256) could be effective in inducing mineralization of rigid bone tissue, as required by Patterson et al., without the aid of any growth factor. The argument is not persuasive. Schiavinato was not relied upon to teach the treatment of the indicated patient population. Callegaro teaches the use of hexadecylamide of hyaluronic acid for local treatment for bone defects, while Schiavinato teaches the specific HYADD™ solution of the instant specification, and Patterson teaches the concept of using hyaluronic acid hydrogels for treatment of bone mineralization. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that Schiavinato '256 refers exclusively to intra-articular treatment, which is entirely excluded in the claimed invention. The argument is not persuasive. Schiavinato is not relied upon for treatment location, but rather for teaching the specific amide derivative of HA. Callegaro teaches the use of hexadecylamide of hyaluronic acid for local treatment for bone defects.
Conclusion
No claims are allowed.
Applicant's 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 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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/SAMANTHA LYNN SCHACHERMEYER/Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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