DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application
Applicants' arguments/remarks filed 12/12/2025 are acknowledged. Claims 1, 41 and 45 are currently amended. Claims 1-2, 6, 10, 14, 16, 18, 20, 26, 31, and 35-47 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment filed 12/12/2025 and with respect to the objection:
The 35 U.S.C. 112(a) rejection of claim 1 has been withdrawn in view of the amendment of claim 1.
Maintained Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1-2, 6, 10, 14, 16, 18, 20, 26, 31, and 3-47 are rejected under 35 U.S.C. 103 as being unpatentable over Mariner et al. (US 20180360970 A1) in view of Auzely-Velty et al. (US 20150283247-Al) and further in view of Balmayor, (Balmayor, Targeted delivery as key for the success of small osteoinductive molecules. Advanced Drug Delivery Reviews 94 (2015) 13–27).
Claims 1, 2, 6, 16,
Mariner et al. teach biomaterials including scaffolds for administration to subjects in need, (Abs), that stimulate bone healing and repair from injuries, (0003), including methacrylated hyaluronic acid (MeHA) to create hydrogel. (0328).
Auzely-Velty et al. teach a composition comprising polymer modified by a bioactive molecule phenylboronic acid (PBA) (Abs), which can bind to molecules having cis-diol units as moieties. A dynamic matrix comprising boronic acid (PBA) as glucose sensor is based on the formation of boronate-cis-diol complexes which are stable at alkaline pH (0004 and 0006). A polymer composition comprising a mixture of a) Phenyl boronic acid (PBA) modified hyaluronic acid (HA) polymer grafted on at least a hydroxyl with a group comprising phenylboronic acid. (Claim 16, pg. 13). "Grafted to" implies covalent conjugation or attachment through covalent bonds.
Balmayor teaches a combination of biomaterials, (pg. 14, left col. 1st par.) drug delivery systems for small osteogenic molecules include Hyaluronic acid (HA) and adenosine or its derivatives (pg. 20, right col., last par.-pg. 21, left col., 1st par.). Adenosine has a cis-diol unit, which can bind to phenylboronic acid (PBA).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare a biomaterial comprising a polymer, methacrylated hyaluronic acid, taught by Mariner et al, a bioactive molecule binding moiety, phenylboronic acid (PBA), which can covalently bind to phenylboronic acid, which then bind to molecules having cis-diol units as moieties taught by Auzely-Velty et al. and an adenosine compound, with diol units taught by Balmayor to form adenosine binding boronate since they have proven that it would be an effective drug delivery system for target delivery for bone treatment.
With regard to claim 10, Balmayor teaches alendronate, a bisphosphonate significant increase in defect site bone volume was observed after treatment with alendronate loaded hydrogel in a non-critical sized femur defect in a rat model. (pg. 18, Table 1, Ref 177).
With regard to claim 14, Balmayor teaches drug delivery systems for small osteogenic molecules include adenosine or its derivatives (pg. 20, right col., last par. - pg. 21, left col., 1st par.).
With regard to claims 16 and 18, Auzely-Velty et al. teach polymer composition comprising a mixture of phenylboronic Acid (PBA) modified hyaluronic acid (HA) polymer for injectable and implantable hydrogel deliveries (Abs) as hydrogel (title), so they can be systemic or local delivery.
With regard to claim 20, Mariner et al. teach that a composition comprising (i) a polymeric biomaterial, methacrylated hyaluronic acid. (0328), which is a pharmaceutically acceptable carrier and/or excipient. (0085).
With regard to claims 26, 31, 35, 36, 37, 39 and 40 a method is in the preamble, an introductory statement and does not give patentable weight to in the invention and not in the body of the claim.
With regard to claims 26, 31, 35, 36, 38, 40, 42 and 43,
Mariner et al. teach a method of treating bone injury, traumatic injury or dental injury comprising administering to a subject in need thereof any of the compositions described above. The compositions and methods may also be used in the context of treating a sports injury, bone repair and regeneration (e.g., healing an injured bone). (0040).
Auzely-Velty et al. teach these hydrogels are also suitable for administration by injection. (0131), and polymer composition comprising a mixture of phenylboronic Acid (PBA) modified polymer for injectable and implantable hydrogel deliveries (Abs) as hydrogel (title), so they can be administered systemic or local delivery. These hydrogels may also be formulated as nanoparticles, which are suitable for administration by injection. (Claim 0131).
Balmayor teaches clinical trials small osteogenic molecules are effective administered systemically to reach the clinical use more promptly. A clear example is bisphosphonate drugs for the treatment of osteoporosis, not to treat a localized bone defect or fracture but the bone as whole. (pg. 23, right col., last par.). Bone healing is a highly complex process involving coordinated responses of the bone marrow, bone cortex, periosteum and the surrounding tissue, with simultaneous osteogenesis and angiogenesis. Efforts are increasingly being towards combinatorial approaches (pg. 20, left col., 2nd last and last par.). Loaded hydrogel enhanced defect site vascularization and new bone formation when administered to a critical sized cranial defect in a rat model. (pg. 17, Table 1, Ref 172.). Local application of the molecule is necessary to realize the full therapeutic effect. (pg. 20, right col, 2nd last par.). A scaffolding material can also be designed to allow for the local delivery. (pg. 21, right col., 2nd par.). Ayukawa et al., who locally injected simvastatin at the defect site on rat tibia resulting in significantly increased new bone formation. The effects, however, did not continue once the administration was terminated. These results indicate that a drug delivery system able to provide a sustained release of simvastatin could be beneficial in this model. (pg. 19, left col. 1st par.). One of ordinary skills in the art can learn from Ayukawa et al., to locally administer the biomaterial to the subject locally at the defect site, or at the bone fracture or a scaffolding material can also be designed to allow for the local delivery. (pg. 21, right col., 2nd par.).
With regard to claims 37, Balmayor teaches the need of either supraphysiological concentrations or repetitive applications in order to exhibit a physiological effect (pg. 13, right col., 1st par.) or administered with a daily dose of 20 mg for a total of 12 weeks. (pg. 23, left col., last par., ref 157).
With regard to claims 39, 41, and 44,
Mariner et al. teach the compositions and methods which may be used in the context of treating bone repair and regeneration (e.g., healing an injured bone). (0040).
Balmayor teaches targeted delivery as key for the success of small osteoinductive molecules, (Title), molecules that are capable of inducing both angiogenesis and osteogenesis simultaneously, preclinical and clinical uses in in treatment bone regeneration of those molecules are described, the needs for the clinical translation of these promising compounds. (Abs) Bisphosphonates have indeed been widely used to treat osteoporosis. (pg. 23, right col., last par.). Alendronate, a bisphosphonate significant increases in defect site bone volume was observed after treatment with alendronate loaded hydrogel in a non-critical sized femur defect in a rat model. (pg. 18, Table 1, Ref 177). Cyclic adenosine monophosphate (cAMP) is playing a role in cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathways (pg. 16, right col, 2nd par.) and is involved in osteogenesis. (pg. 19, right col, 2nd par.). Adenosine and its derivatives have been described as having an impact on multipotent mesenchymal stem cells (MSCs) differentiation. Adenosine is an endogenous signaling nucleoside that can be formed intracellularly by the metabolism of adenosine triphosphate (ATP) or from the extracellular metabolism of adenine nucleotides. Adenosine can bind all four G protein coupled receptors commonly found in variety of cell types. Osteogenesis and chondrogenesis as well as for adipogenesis stimulation of MSCs have found by using adenosine molecules. Adenosine signaling is linked with angiogenesis. All four adenosine receptors have promoted angiogenesis. Adenosine or adenosine derivatives can induce the expression of VEGF in a variety of cell types and stimulate endothelial cell migration, proliferation and tubular formation. Some adenosine compounds have potential stimulators of bone formation. All four adenosine receptors are present in human osteoblasts cultures. Agonists of all adenosine receptors increased the proliferation of osteoblasts in a concentration dependent manner. cAMP analogues also present clear osteogenic properties. The cAMP/PKA signaling pathway is involved in osteogenesis. The molecule 8-Br-cAMP (an analog of adenosine) as enhancer of both angiogenesis and osteogenesis in vitro. 8-Br-cAMP stimulated VEGF secretion and significantly increased matrix mineralization and calcium levels. Others have reported the same molecule as stimulator of adipogenic and/or osteogenic differentiation. Sufficient scientific evidence support the association of adenosine signaling to angiogenesis and also to osteogenesis. It is feasible that adenosine compounds stimulate these two processes concomitantly. (pg. 20, right col, last par.-pg. 21, left col., 1st and 2nd par.). Bisphosphonates in granules or has been found reduction in the number of osteoclasts in vitro and in hydrogel significant increase in defect site bone volume was observed after treatment with alendronate loaded hydrogel in a non-critical sized femur defect in a rat model. (Table 1, pg. 18).
Claims 45,
Mariner et al. teach biomaterials including scaffolds for administration to subjects in need, (Abs), that stimulate bone healing and repair from injuries, (0003), including methacrylated hyaluronic acid (MeHA) to create hydrogel. (0328).
Auzely-Velty et al. teach a composition comprising polymer modified by a bioactive molecule phenylboronic acid (PBA) (Abs), which can bind to molecules having cis-diol units as moieties. A dynamic matrix comprising boronic acid (PBA) as glucose sensor is based on the formation of boronate-cis-diol complexes which are stable at alkaline pH (0004 and 0006). Upon diol addition, it is stated that only the charged state (2) forms a stable complex with diol through reversible covalent bonding. (0202). Adenosine has diol group, so boronate can form reversible covalent bonding with diol group of adenosine.
Balmayor teaches a combination of biomaterials, (pg. 14, left col. 1st par.) drug delivery systems for small osteogenic molecules include Hyaluronic acid (HA) and adenosine or its derivatives (pg. 20, right col., last par.-pg. 21, left col., 1st par.). Adenosine has a cis-diol unit, which can bind to phenylboronic acid (PBA).
With regard to claim 46,
Balmayor teaches targeted delivery as key for the success of small osteoinductive molecules. (Title). Bisphosphonates which appear to have a specifically high affinity to CaP crystals. Seshima et al. used HA granules loaded with bisphosphonates and observed that the release of bisphosphonates was dependent on the HA solubility. (pg. 22, left col., 2nd last par.). Bisphosphonates (BP): Pamidronate or Alendronate. (Table 1, pg. 18).
With regard to claim 47,
Auzely-Velty et al. teach polymer composition comprising a mixture of phenylboronic Acid (PBA) modified hyaluronic acid (HA) polymer for injectable and implantable hydrogel deliveries (Abs) as hydrogel (title), so they can be systemic or local delivery.
Response to Arguments
35 U.S.C. § 103 Rejection Claims 1-2, 6, 10, 14, 18, 20, 26, 31, and 35-47
Applicant argues about The Failure of the References to Teach or Suggest the Claimed Elements: applicant does not dispute the fact that references can be combined to establish prima facie obviousness of a claim or that the skilled person can rely on one reference more heavily than another, but applicant points out that Mariner, Auzely-Velty and Balmayor besides teaching what applicant recites in claims’ limitations, they also teach things differently from what applicant recites in claims’ limitations, which Applicant lists on page 7 of Arguments/remarks and applicant states that.
Applicant's arguments have been fully considered but they are not persuasive because applicant lists other topics to argue that they are as nonanalogous arts, but it has been held that a prior art reference must either be in the field of the inventor' s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992).
Mariner et al. teach biomaterials including scaffolds for administration to subjects in need, (Abs), that stimulate bone healing and repair from injuries, (0003), including methacrylated hyaluronic acid (MeHA) to create hydrogel. (0328).
Auzely-Velty et al. teach a composition comprising polymer modified by a bioactive molecule phenylboronic acid (PBA) (Abs), which can bind to molecules having cis-diol units as moieties. A dynamic matrix comprising boronic acid (PBA) as glucose sensor is based on the formation of boronate-cis-diol complexes which are stable at alkaline pH (0004 and 0006). A polymer composition comprising a mixture of a) Phenyl boronic acid (PBA) modified hyaluronic acid (HA) polymer grafted on at least a hydroxyl with a group comprising phenylboronic acid. (Claim 16, pg. 13). "Grafted to" implies covalent conjugation or attachment through covalent bonds.
Balmayor teaches a combination of biomaterials, (pg. 14, left col. 1st par.) drug delivery systems for small osteogenic molecules include Hyaluronic acid (HA) and adenosine or its derivatives (pg. 20, right col., last par.-pg. 21, left col., 1st par.). Adenosine has a cis-diol unit, which can bind to phenylboronic acid (PBA).
One with ordinary skill in the art has the capability to learn from and to select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of those alternatives. And prior arts teach more do not negate its teaching of the claimed subject matter.
Applicant argues about The Failure of the References to Suggest To or Motivate the Skilled Person to Combine and/or Modify the Teachings to Arrive at the Claimed Subject Matter that one with skill in the art can pull right elements among non-analogous field, unless only possible through the application of impermissible hindsight reasoning from prior arts.
Applicant's arguments have been fully considered but they are not persuasive. In response to applicant' s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). One with skill in the art, is known for solving the same problem, is represented with design choices, may modify the teachings of the prior arts until they can achieve better outcome results. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Since Mariner teaches methacrylated hyaluronic acid (MeHA) to create hydrogel. Auzely-Velty et al. teach a composition comprising polymer modified by a bioactive molecule phenylboronic acid (PBA), which can bind to molecules having cis-diol complexes, which are a well-established, dynamic, and reversible crosslinking method used to create multifunctional hyaluronic acid (HA) hydrogels for biomedical applications. Balmayor teaches a combination of biomaterials, include Hyaluronic acid (HA) and adenosine or its derivatives, which have a cis-diol unit, which can bind to phenylboronic acid (PBA). Other nucleosides or saccharides besides adenosine can be a choice also. But the choice is to select one with a cis-diol unit.
Applicant argues about The Failure of the References to Provide the Skilled Person with a Reasonable Expectation of Successfully Arriving at the Claimed Subiect Matter
Applicant's arguments have been fully considered but they are not persuasive because When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012).
Conclusion
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Correspondence
No claim is allowed
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/NGOC-ANH THI NGUYEN/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615