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
Claims 1, 2, and 4-20 are pending.
Claims 1, 2, and 4-20 are under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 2, and 4-20 have an earliest effective filing date of 01/12/2023, corresponding to PRO 63/479,605.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/01/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections
35 U.S.C. 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4-6, and 8-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Claims 1, 4, and 5 are drawn to methods of 1) treating osteoarthritis (OA), 2) reducing cartilage degradation, and 3) treating or preventing subchondral bone sclerosis), and said methods require the administration of a CD14 inhibitor that neutralizes or blocks CD14, inhibits CD14 function, inhibits CD14 production, or a combination thereof. The claims encompass a large genus of molecules that inhibit CD14, and following a review of the disclosure, it appears that four species comprised within the claimed genus have been described, specifically, Atibuclimab, recombinant thrombomodulin (rTMD23), microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN), or iMAP2K3. However in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to at least encompass small molecule inhibitors of CD14, nucleic acid and peptide inhibitors of CD14, and anti-CD14 antibodies. Even though Applicant has disclosed four species within said genus, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which small molecules, nucleic acids, peptides, and antibodies function as inhibitors of CD14. Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In the instant case, Applicant has disclosed four species within the genus claimed; however given the substantial antibody structure variation within the genus, as well as the high level of unpredictability in the art, the disclosure of four species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore Applicant has not disclosed relevant, identifying characteristics of small molecules, nucleic acids, peptides, and/or antibodies that function as inhibitors of CD14. Absent a description of the at least minimal structural features correlating with a functional ability to inhibit CD14 which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which small molecules, nucleic acids, peptides, and antibodies function as inhibitors of CD14.
Although screening techniques can be used to isolate small molecules, nucleic acids, peptides, and/or antibodies that function as inhibitors of CD14, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
With respect to claims 13-18, these claims recite various characteristics of the claimed method. These claims recite that the claimed method does not alter the concentration of serum cytokines, RANK L, CCL12, Leptin, TNF-alpha, IL-10 or sCD14. These claims also recite that the administered CD14 inhibitor 1) reduces fibrosis without altering synovial hyperplasia or cellularity in the subject and 2) preserves articular cartilage (in the femur or tibia). Paragraph [0100] of the published application discloses that anti-CD14 treatment of OA did not significantly alter the concentration of serum cytokines, RANK L, CCL12, Leptin, TNF-alpha, IL-10 or sCD14. Paragraph [0102] of the published application discloses that anti-CD14 treatment 1) reduced fibrosis without altering synovial hyperplasia or cellularity in the subject and 2) preserved articular cartilage (in the femur or tibia). While the administration of some anti-CD14 antibodies would likely result in one or more of the claimed characteristics, other anti-CD14 antibodies would likely fail to provide said characteristics. The specification does not provide any general structure of anti-CD14 antibodies by disclosure of relevant, identifying features that correlates with the claimed functional characteristics. This is a significant omission, because the ability of an antibody to bind a particular antigen, alone, does not characterize what other properties the antibody may or may not possess. It is well-recognized in the art that antibodies will display markedly different and unpredictable properties depending on the epitope in an antigen to which a particular antibody specifically binds. Stancovski et al. (PNAS, 88: 8691-8695, 1991) developed a panel of monoclonal antibodies specific to HER-2, an art-known tumor antigen, and Stancovski et al. discovered that although each antibody bound the HER-2 antigen, said antibodies displayed a range of different properties, see Abstract and p. 8694, Table 1. Two of the anti-HER-2 antibodies almost completely inhibited tumor growth, two anti-HER-2 antibodies displayed moderate inhibitory effects, and yet another anti-HER-2 antibody accelerated tumor growth, p. 8694, Table 1. Additionally, said panel of anti-HER-2 antibodies demonstrated a range of apparent affinities and a range of abilities to induce complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and tyrosine phosphorylation, p. 8694, Table 1, and p. 8692, second column, second full paragraph. Furthermore, similar to Stancovski et al., Jiang et al. (J. Biol. Chem., 280: 4656-4662, 2005) teach that while many anti-HER-2 antibodies inhibit the proliferation of cancer cells, other anti-HER-2 antibodies actively stimulate cancer growth, see p. 4656, second column, final paragraph. Importantly, Jiang et al. add that “[i]t is well known that different biological effects are associated with the epitope specificity of the antibodies.” See p. 4656, second column, final paragraph. Based upon the teachings of Stancovski et al. and Jiang et al., one skilled in the art would reason that antibodies specific for the same target protein may have different effects depending upon the epitope specificity of a particular target protein-specific antibody. Accordingly in view of these teachings and absent evidence to the contrary, one skilled in the art would appreciate that the functional characteristics of antibodies binding to the same antigen will differ significantly depending upon epitope specificity, and as such in the absence of screening methodologies, one skilled in the art would be unable to determine whether a particular anti-CD14 antibody is capable providing the recited functional characteristics.
Accordingly given the unpredictability in the art and given the lack of particularity with which the claimed CD14 inhibitors are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
35 U.S.C. 103
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, 2, 4-6, and 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (Seminars in Immunopathology, 41: 583-594, 2019).
Miller et al. teach that “[o]steoarthritis (OA) is a chronic progressive, painful disease of synovial joints, characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovitis. It is now widely appreciated that the innate immune system, and in particular Toll-like receptors (TLRs), contributes to pathological changes in OA joint tissues. Furthermore, it is now also increasingly recognized that TLR signaling plays a key role in initiating and maintaining pain.” See Abstract.
At p. 585, Miller et al. teach that “TLRs are transmembrane receptors that facilitate inflammatory signaling in response to PAMPs [pathogen-associated molecular patterns] and DAMPs [damage-associated molecular patterns]. In humans, TLR1, 2, 4, 5, and 6 are found on the cell membrane, while TLR3, 7, 8, and 9 are located in endosomes. TLR2 exists as a homodimer, and also as a heterodimer in complex with TLR1 or TLR6. Several DAMPs found in the osteoarthritic joint and discussed in this review can interact with the cell surface TLRs, including extracellular matrix components (e.g., biglycan, fibronectin (Fn) fragments, and an aggrecan-derived peptide—Ag 32-mer), and molecules produced directly by cells under stress (e.g., HMGB1, S100A8/9). In addition, low levels of the TLR4 ligand lipopolysaccharide (LPS) are found in OA joint fluids. A number of co-receptors or co-factors can modify the nature of TLR/ligand interactions. These include the soluble co-factors LBP and MD2 which facilitate LPS/TLR4 signaling, the receptor CD44 which can modulate the response to TLR2/4 ligands, and CD14 which can modulate the strength/sensitivity of TLR signaling and is active both in membrane and soluble form (emphasis added).”
At p. 590, Miller et al. teach that “[t]he evidence supporting a role for TLR pathways in OA is also leading to the identification of surrogate markers of disease severity and pathology. Several co-receptors are required for LPS to optimally activate TLR4-signaling, including LPS binding protein (LBP), MD-2, and CD14. LBP and MD-2 are secreted proteins, while CD14 is found as a GPI-anchored membrane protein and as a soluble form generated during macrophage activation. Our group demonstrated that SF sCD14 levels in OA patients are elevated compared to controls. In addition, the soluble form remains biologically active, as it can augment TLR signaling in endothelial cells and synoviocytes. Daghestani et al. subsequently reported that SF sCD14 levels were associated with density of activated macrophages in the joint capsule/synovium measured semi-quantitatively on SPECT/CT images, consistent with its primary cellular source. This study also found that SF sCD14 was associated with several clinical measures of disease severity, including severity of knee pain and joint space narrowing, and was predictive of osteophyte progression in a cohort of patients (emphasis added)…”
At p. 591, Miller et al. teach that “[c]linical grade reagents already exist to modulate TLR pathways through these different approaches. As examples, antibodies targeting TLR4 (NI-0101) have already been in phase 1 clinical trials for rheumatoid arthritis…, and anti-CD14 antibodies are currently being tested in neurodegenerative disease and lung injury... To our knowledge, none have been tested in OA. Given the mounting evidence for TLR pathways both at the preclinical and clinical level, and availability of therapeutics targeting these pathways, the likelihood of future work in this area leading to clinically effective new therapies is high.”
In view of the teachings of Miller et al., one of ordinary skill in the art would have been motivated to treat osteoarthritis by administering to a subject in need thereof a therapeutically effective amount of a CD14 inhibitor, wherein the therapeutically effective amount of the CD14 inhibitor neutralizes or blocks CD14, inhibits CD14 function, inhibits CD14 production, or a combination thereof, thereby treating osteoarthritis or preventing the development of osteoarthritis after a joint injury in the subject. One of ordinary skill in the art would have been motivated to do so, because Miller et al. teach that TLRs contribute to OA pathology. Miller et al. further teach that CD14, which is elevated in the synovial fluid of OA patients and associated with several clinical measures of disease severity, can modulate the strength/sensitivity of TLR signaling, and Miller et al. teach that anti-CD14 antibodies are in use for modulating TLR pathways. Based upon these teachings, one of ordinary skill in the art would have been motivated to administer a CD14 inhibitor, such as an anti-CD14 antibody, to OA patients, because there would have been a reasonable expectation that such a method would provide a therapeutic benefit. Miler et al. even provide motivation for exploring TLR modulation in the treatment of OA - “Given the mounting evidence for TLR pathways both at the preclinical and clinical level, and availability of therapeutics targeting these pathways, the likelihood of future work in this area leading to clinically effective new therapies is high.” Miller et al. therefore renders claim 1 prima facie obvious.
With respect to claims 2 and 11, one of ordinary skill in the art would appreciate that treating a disease or condition generally involves ameliorating the symptoms of said disease or condition, such as pain. As indicated above Miller et al. teach that “it is now also increasingly recognized that TLR signaling plays a key role in initiating and maintaining pain.”
With respect to claims 4-6, in view of the teachings of Miller et al., there would have been a reasonable expectation that the administration of a CD14 inhibitor is capable of reducing cartilage degradation and treating or preventing subchondral bone sclerosis, at least because cartilage degradation and subchondral bone sclerosis are two known hallmarks of OA that are influenced by inflammation - “Cartilage degradation, subchondral bone remodeling, and osteophyte formation are the hallmarks of OA, but there is also low-grade synovitis, and involvement of periarticular structures and-in the knee-the menisci. There is a strong mechanical component in OA pathogenesis, but it is now also widely appreciated that the interplay between mechanical factors and low-grade inflammation is a key driver for progressive joint damage. Several lines of evidence, both in clinical samples and in animal models, suggest that low-grade inflammation contributes to pathological changes in all OA joint tissues, mainly mediated by the innate immune system (macrophages, complement system) (emphasis added).”
With respect to claims 9 and 10, one of ordinary skill in the art would reason that the method rendered obvious by the teachings of Miller et al. would limit inflammation-induced OA in various species, including at least humans and non-human primates.
With respect to claim 12, it would have been prima facie to identify a subject as having OA prior to treating said subject for OA.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by Miller et al.
Claims 7, 8, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (Seminars in Immunopathology, 41: 583-594, 2019), as applied to claims 1, 2, 4-6, and 9-12, and further in view of Henderson et al. (Medicine, 100(42): 1-9, 2021).
As indicated above in view of the teachings of Miller et al., one of ordinary skill in the art would have been motivated at the effective filing date of the invention to treat osteoarthritis by administering to a subject in need thereof a therapeutically effective amount of a CD14 inhibitor, wherein the therapeutically effective amount of the CD14 inhibitor neutralizes or blocks CD14, inhibits CD14 function, inhibits CD14 production, or a combination thereof, thereby treating osteoarthritis or preventing the development of osteoarthritis after a joint injury in the subject. Miller et al. do not teach the CD14 inhibitor atibuclimab; however this deficiency is remedied by Henderson et al.
Henderson et al. teach that “[c]luster of differentiation 14 (CD14) is a glycoprotein found on the surface of myeloid cells and as a soluble protein in plasma. It functions as an accessory molecule for several toll-like receptors (TLRs), a family of pattern recognition receptors that respond to conserved patterns in pathogens and human molecules associated with inflammation and tissue injury… Elevated levels of circulating soluble CD14 (sCD14) have been described in ALS and are associated with (and predictive of) a rapid rate of disease progression and a poor clinical prognosis. Elevated sCD14 levels are positively correlated with ALS disease severity scores. CD14 plays an important role in the initiation of innate and chronic inflammatory cascades, including chronic inflammation… Monoclonal antibody against CD14 (IC14) (atibuclimab) is a chimeric monoclonal antibody directed against CD14 and is composed of murine variable and human IgG4 Fc regions. It recognizes both membrane-bound CD14 (mCD14) and sCD14 and is non-lytic. IC14 has been administered to over 150 healthy volunteers and patients with sepsis, community-acquired pneumonia, or acute lung injury at cumulative doses of up to 16mg/kg over 4 to 5 days and has been generally well tolerated.” See p. 2. At the Abstract, Henderson et al. teach that IC14 (atibuclimab) may be administered intravenously.
In view of the teachings of Miller et al. and Henderson et al., one of ordinary skill in the art would have been motivated at the effective filing date of the invention to treat osteoarthritis by administering to a subject in need thereof a therapeutically effective amount of a CD14 inhibitor, wherein the therapeutically effective amount of the CD14 inhibitor neutralizes or blocks CD14, inhibits CD14 function, inhibits CD14 production, or a combination thereof, thereby treating osteoarthritis or preventing the development of osteoarthritis after a joint injury in the subject. One of ordinary skill in the art would have been motivated to do so, because Miller et al. teach that TLRs contribute to OA pathology. Miller et al. further teach that CD14, which is elevated in the synovial fluid of OA patients and associated with several clinical measures of disease severity, can modulate the strength/sensitivity of TLR signaling, and Miller et al. teach that anti-CD14 antibodies are in use for modulating TLR pathways. Based upon these teachings, one of ordinary skill in the art would have been motivated to administer a CD14 inhibitor, such as an anti-CD14 antibody, to OA patients, because there would have been a reasonable expectation that such a method would provide a therapeutic benefit. Miler et al. even provide motivation for exploring TLR modulation in the treatment of OA - “Given the mounting evidence for TLR pathways both at the preclinical and clinical level, and availability of therapeutics targeting these pathways, the likelihood of future work in this area leading to clinically effective new therapies is high.” Furthermore Henderson et al. teach that atibuclimab is an anti-CD14 antibody that may be used to limit innate and chronic inflammatory cascades in ALS, a disease that involves chronic inflammation associated with elevated levels of sCD14. Given that OA is also a disease that involves chronic inflammation associated with elevated levels of sCD14, one of ordinary skill in the art would have been motivated to treat OA with atibuclimab, because there would have been a reasonable expectation that said method would ameliorate the effects of CD14-driven inflammation, thereby providing a therapeutic benefit. The invention of Miller et al. and Henderson et al. meets the limitations of claims 7, 19, and 20.
With respect to claims 8, as indicated above, Henderson et al. teach that IC14 (atibuclimab) may be administered intravenously.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the cited references.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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