CTNF 18/270,368 CTNF 88556 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 the Claims Claims 1-2, 5-6, 9-14, 16-17, 19, 21-23, 27-28, 37, and 40 are pending (claim set as filed on 06/29/2023). Priority This application is a 371 of PCT/US2022/011109 filed on 01/04/2022, which has a provisional application no.: 63/134,062 filed on 01/05/2021. Drawings The drawings filed on 06/29/2023 have been accepted. Information Disclosure Statement 06-52 The Information Disclosure Statement (IDS) submitted on 06/29/2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the Examiner. Claim Rejections - 35 USC §112, Failing to Further Limit 07-36 The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS - Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claims 2 and 6 are rejected under 35 U.S.C. 112(d) 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. Claim 2 recites contacting MSCs, ADSCs, and/or MPCs with an amount effective of FGF8 to enhance myogenic and/or chondrogenic lineage commitment and therefore, fails to further limit it base claim 1 because it already has this limitation. In other words, it appears to be a duplicate limitation and does not further narrower the scope of its base claim. Similarly, claim 6 also fails to further limit it base claim 5 because it already has the limitation of contacting MSCs, ADSCs, and/or MPCs with an amount effective of FGF8 to suppress adipogenic and/or tenogenic differentiation of the MSCs, ADSCs, and/or MPCs. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections - 35 USC §102, Anticipation 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention. 07-15 AIA Claim s 1-2, 5-6, 11-14, 16-17, 19, and 27 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Mengsteab (Mechanically superior matrices promote osteointegration and regeneration of anterior cruciate ligament tissue in rabbits, with a publication date of 11/17/2020 (within one year grace period of the instant provisional filing date) - reference cited by the ISA and in the IDS filed on 06/29/2023) . Mengsteab ’s general disclosure relates to the treatment for anterior cruciate ligament (ACL) reconstruction (see abstract). Mengsteab discloses “this study aims to 1) accelerate ACL regeneration by supplementing the bioengineered ACL matrix with bone marrow aspirate concentrate (BMAC) and growth factors (bone morphogenetic protein 2 [BMP-2], fibroblast growth factor 2 [FGF-2], and FGF-8 ); and 2) increase the strength retention of the bioengineered ACL matrix by incorporating nondegradable polyethylene terephthalate (PET) yarns” (see page 28655, right col.). Regarding the claim limitations pertaining to the in vivo contacting or administration of FGF8, Mengsteab teaches “intraarticular treatment with FGF-2 and FGF-8 was found to suppress joint inflammation” and “the combinatorial application of FGF-2 and FGF-8 in the knee joint suppresses inflammation by reducing adipokine secretion” (see abstract & page 28655, right col.). FGF-8 would accelerate ligamentization of the bioengineered ACL matrix by promoting the proliferation of progenitor cells and dedifferentiation of mature cells in the synovial environment (see page 28656, left col.). Regarding claim 11 pertaining to the mammalian cell source, Mengsteab teaches bone marrow aspirate (BMA) was isolated from the femur and tibia of each rabbit (see page 28656: Results). Regarding claim 13 , claim interpretation : a wherein or whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited (MPEP 2111.04(I)). If the prior art teaches the same physical steps and conditions as in the claims, then the results or intended outcome should be inherent. Regarding claims 14 and 16-17 pertaining to the osteoarthritis, Mengsteab teaches “we hypothesize that the application of FGF-8 in this study may have inhibited adipogenesis in the knee leading to the reduced inflammatory synovial fluid profile observed. Increasing evidence suggests that leptin, a hormone secreted by adipocytes, plays a role in the pathogenesis of osteoarthritis by stimulating an inflammatory environment in the knee” (see page 28663, right col.). Mengsteab teaches intraarticular treatment with FGF-8 (see page 28655, right col.). Regarding claims 14 and 19 pertaining to the rotator cuff injury, Mengsteab teaches the ability of BMAC to enhance the repair of damaged rotator cuff and meniscus tissues has been demonstrated in rabbit models (see page 28655, right col.) . 07-15 AIA Claim s 1-2, 5-6, 9-14, 16-17, and 27-28 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Broeckx (US 2016/0289639 A1) . Broeckx ’s general disclosure relates to the field of methods and compositions for directed mesenchymal progenitor cells cultivated in vitro to differentiate into specific cell lineage pathways, and particularly to such directed lineage induction prior to, or at the time of, their implantation into a recipient or host for the therapeutic treatment of pathologic conditions in humans and other species (see ¶ [0001], [0008]-[0010]). Regarding claims 1-2 , 5-6 , and 9-10 pertaining to an in vitro culture, Broeckx teaches “In a first aspect, the invention provides a cell medium for in vitro inducing chondrogenesis or tenogenesis in mesenchymal stem cells (MSCs)” (see ¶ [0036] and see claim 18). Broeckx teaches a cell medium and method for inducing chondrogenesis or tenogenesis in isolated mesenchymal stem cells (MSCs) wherein the inducing medium comprises a glucose medium supplemented with at least one growth factor, said growth factor is chosen from the group of fibroblast growth factors (FGF) or the group of transforming growth factors (TGF) (see ¶ [0009], [0028], [0045], [0082]). Broeckx further teaches the FGF is chosen from the group of FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8 , FGF-9, FGF-10 or any combination thereof (see ¶ [0046]-[0058]). Regarding claim 11 pertaining to the mammalian MSCs source, Broeckx teaches “the stem cells used in the present invention are isolated from the blood of mammals, more preferably, from peripheral blood. By preference the used blood will originate from human, cat, dog or horse, most preferably equine derived” (see ¶ [0088]). Regarding claims 12-14 , 16-17 , and 27-28 pertaining to an in vivo administration to treat a disorder, Broeckx discloses that “damage to the articular surfaces of synovial joints, or tendon and ligament lesions can arise from trauma, from diseases (e.g. osteoarthritis), and as a result of the aging process” (see ¶ [0003]). Broeckx further teaches “the composition is formulated for intravenous, intra-articular, intramuscular, intra-lesional administration to mammals. These modes of administration will depend heavily on the desired application of stem cells and/or their differentiated form” (see ¶ [0093]-[0098]). Broeckx teaches the “application whereby a subject benefits from administering the composition to said subject. The subject may include a horse, cat, dog or human” (see ¶ [0099], Example 4) . 07-15 AIA Claim s 1-2, 5-6, 12-13, 23, 27-28, 37, and 40 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Cornish (US 2004/0266680 A1) . Cornish ’s general disclosure relates to the discovery that FGF-8 can stimulate proliferation of osteoblasts, which are known to play a role in mediating or modulating bone growth (see ¶ [0005]). Cornish discloses that fibroblast growth factors (FGF) specify the differentiation, patterning, and proliferation of a variety of tissues (see ¶ [0002]). FGF-8 has been shown to modulate chondrogenesis (see ¶ [0003]). Regarding claims 1-2 , 5-6 , 12, and 27 pertaining to contacting in vivo , Cornish teaches a method for treating a bone condition in a patient comprising administering an effective amount of FGF-8 , FGF-8 analog, or a FGF-8 agonist to the patient (see abstract & ¶ [0031]-[0032]). Regarding claim 13 , claim interpretation : a wherein or whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited (MPEP 2111.04(I)). If the prior art teaches the same physical steps and conditions as in the claims, then the results or intended outcome should be inherent. Nonetheless, note that Cornish discloses that fibroblast growth factors (FGF) promote the proliferation of a variety tissues (see ¶ [0002]). Regarding claim 23 pertaining to the FGF8 source, Cornish teaches FGF-8b isoform displays the most potent mitogenic activity in vitro (see ¶ [0003]). Cornish teaches human, mouse, or rat FGF8 polypeptides (see ¶ [0008]-[0014]). Regarding claim 28 pertaining to the mammalian subject, Cornish teaches the patient may be a human, a horse, a dog, or a cat (see ¶ [0006]). Regarding claims 37 and 40 pertaining to the FGF8 polypeptide sequence, Cornish teaches that “FGF-8a” is an isolated polypeptide of 204 amino acids in length. It includes mouse FGF-8a, rat FGF-8, and human FGF-8a, the sequences of which are shown below. Mouse FGF-8a (SEQ ID NO: 1) (see ¶ [0008]-[0015]). Claim interpretation : SEQ ID NO: 1 of the prior art corresponds with SEQ ID NO: 2 of the instant application as shown in the alignment below: PNG media_image1.png 356 664 media_image1.png Greyscale Claim Rejections - 35 USC §103, Obviousness 07-20-aia AIA 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. 07-23-aia AIA The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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. 07-21-aia AIA Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Broeckx in view of Cornish as applied to the claims above, and Peterson (US 2015/0231183 A1) . Broeckx ’s disclosure is taught above as it relates to culturing MSCs in a culture medium comprising FGF-8 which are useful for either tenogenesis or chondrogenesis (see ¶ [0107]). Broeckx further teaches formulating compositions thereof with broad applicability including treatment of trauma of cartilage, tendon, ligament, bones, osteoarthritis, et. al. (see ¶ [0093]-[0099]). However, Broeckx does not teach: wherein the mammalian subject has a rotator cuff injury and administering FGF-8 to or proximal to the rotator cuff ( claim 19 ). Cornish ’s disclosure is taught above which discloses that fibroblast growth factors (FGF) specify the differentiation, patterning, and proliferation of a variety of tissues (see ¶ [0002]). FGF-8 has been shown to modulate chondrogenesis (see ¶ [0003]). Moreover, Cornish teaches the administration of an effective amount of FGF-8 in vivo (see ¶ [0019], [0031]-[0032]). Peterson discloses compositions comprising multipotent cells and a method thereof for treating tissue injury and diseases such osteoarthritis (see ¶ [0003], [0021]). “Injuries to soft tissues, such as muscles, tendons, ligaments, and joint capsules, occur quite frequently … Even despite surgical repair, about 15% of Achilles tendon and 40% of two tendon rotator cuff repairs subsequently fail” (see ¶ [0005]). Peterson teaches “a variety of growth factors have been used to improve tissue growth and migration to the wound site, as well as to promote angiogenesis” (see ¶ [0007]-[0008]). Peterson teaches FGF-8, FGF-9, or FGF-18 have been shown to have chondrogenic effect in vivo (see page 25: Table 15). It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to envisage the treatment of a rotator cuff injury following the guidance of the cited references. The primary reference of Broeckx teaches “the composition according to the present invention has very broad applicability” including treatment of trauma of cartilage, tendon, ligament, bone, et. al. (see Broeckx at ¶ [0095]-[0099]) and Peterson suggests soft tissue injuries include tendon rotator cuff repair (see Peterson at ¶ [0003]-[0005]). It would have been further obvious to administer FGF-8 to or proximal to the rotator cuff as Peterson discloses “other routes of administration can be used in additional embodiments, including direct administration (either to a tissue surface or by direct injection)” (see Peterson at ¶ [0013]). The ordinary artisan would have had a reasonable expectation of success is because Cornish discloses that fibroblast growth factors (FGF) specify the differentiation, patterning, and proliferation of a variety of tissues (see ¶ [0002]). Thus, the administration of FGF-8 to the rotator cuff site of injury for repair would have been readily apparent to one of ordinary skill in the following the guidance of the cited references . 07-21-aia AIA Claim s 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Broeckx in view of Cornish as applied to the claims above, and Gronthos (US 2015/0072422 A1) . Broeckx ’s disclosure is taught above as it relates to culturing MSCs in a culture medium comprising FGF-8 which are useful for either tenogenesis or chondrogenesis (see ¶ [0107]). Broeckx further teaches formulating compositions thereof with broad applicability including treatment of trauma of cartilage, tendon, ligament, bones, osteoarthritis, et. al. (see ¶ [0093]-[0099]). However, Broeckx does not teach: wherein the mammalian subject has a paraspinal injury and administering FGF-8 to the spine or to fat pads of the spine ( claims 21-22 ). Cornish ’s disclosure is taught above which discloses that fibroblast growth factors (FGF) specify the differentiation, patterning, and proliferation of a variety of tissues (see ¶ [0002]). FGF-8 has been shown to modulate chondrogenesis (see ¶ [0003]). Moreover, Cornish teaches the administration of an effective amount of FGF-8 in vivo (see ¶ [0019], [0031]-[0032]). Gronthos ’ general disclosure relates to methods of enhancing proliferation and/or survival of mesenchymal precursor cells (MPC) and/or progeny derived therefrom in vitro or in vivo (see abstract). Gronthos teaches the cellular compositions may be used to treat patients with a cartilage condition, for example, rheumatoid arthritis or osteoarthritis or a traumatic or surgical injury to cartilage and other examples of bone conditions include meniscal tears, spinal fusion, spinal disc removal, spinal reconstruction, bone fractures, bone/spinal deformation, osteosarcoma, myeloma, bone dysplasia, scoliosis, osteoporosis et. al. (see ¶ [0092], [0150]). Gronthos teaches “Routes of administration of the cells of the invention or compositions or components (e.g., ECM, cell lysate, conditioned medium) thereof include intramuscular, ophthalmic, parenteral, intraarterial, subcutaneous, oral, and nasal administration. Particular routes of parenteral administration include, but are not limited to, intramuscular, subcutaneous, intraperitoneal, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal and/or peri-spinal routes of administration” (see ¶ [0154]). It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to envisage the treatment of a paraspinal injury following the guidance of the cited references. The primary reference of Broeckx teaches “the composition according to the present invention has very broad applicability” including treatment of trauma of cartilage, tendon, ligament, bone, et. al. (see Broeckx at ¶ [0095]-[0099]) and Gronthos discloses conditions involving the spinal column (see Gronthos ¶ [0092], [0150]). It would have been further obvious to administer FGF-8 to the spine or to fat pads of the spine as Gronthos discloses the routes of administration may include subcutaneous, intrathecal, intracisternal, intraspinal and/or peri-spinal routes of administration (see Gronthos at ¶ [0154]). The ordinary artisan would have had a reasonable expectation of success is because Cornish discloses that fibroblast growth factors (FGF) specify the differentiation, patterning, and proliferation of a variety of tissues (see ¶ [0002]). Thus, the administration of FGF-8 to the spine site of injury for repair would have been readily apparent to one of ordinary skill in the following the guidance of the cited references. Conclusion No claims were allowed. Correspondence Information Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGHI V NGUYEN whose telephone number is (571)270-3055. The examiner can normally be reached Mon-Fri: 9 - 3 pm (ET). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /NGHI V NGUYEN/Primary Examiner, Art Unit 1653 Application/Control Number: 18/270,368 Page 2 Art Unit: 1653 Application/Control Number: 18/270,368 Page 3 Art Unit: 1653 Application/Control Number: 18/270,368 Page 4 Art Unit: 1653 Application/Control Number: 18/270,368 Page 5 Art Unit: 1653 Application/Control Number: 18/270,368 Page 6 Art Unit: 1653 Application/Control Number: 18/270,368 Page 7 Art Unit: 1653 Application/Control Number: 18/270,368 Page 8 Art Unit: 1653 Application/Control Number: 18/270,368 Page 9 Art Unit: 1653 Application/Control Number: 18/270,368 Page 10 Art Unit: 1653 Application/Control Number: 18/270,368 Page 11 Art Unit: 1653 Application/Control Number: 18/270,368 Page 12 Art Unit: 1653 Application/Control Number: 18/270,368 Page 13 Art Unit: 1653