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 1-20 are pending in the present application.
Election/Restrictions
Applicant's election with traverse of a species of TNAP inhibitor: a small molecule in the reply filed on August 27, 2025 is acknowledged. The traversal is on the ground(s) that the distinct species of TNAP inhibitors are features of the present claims. This is not found persuasive because the claims (and species/features) are unpatentable over the prior art as indicated below in the rejection under 35 U.S.C. 103.
The requirement is still deemed proper and is therefore made FINAL.
As per MPEP 803.02, the examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species is not allowable over the prior art as indicated in the rejection under 35 U.S.C 10-.
As the Applicant’s elected species has been found not allowable, the Markush-type claims have been rejected and claims to the nonelected invention held withdrawn from further consideration. Claims 1-3 and 5-20 have been examined to the extent that they embrace and are readable on the elected embodiment and the above identified nonelected species. Claims 1-3 and 5-20 have been found to be not allowable over the prior art.
Claim 4 is withdrawn from consideration by the Examiner under 37 CFR 1.142(b) as being drawn to a non-elected invention.
Priority
The following continuity data is acknowledged in the present application file:
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Information Disclosure Statement
The Information Disclosure Statement(s) filed March 09, 2023 have been acknowledged by the Examiner. 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
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 7 is rejected 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.
Claim 7 recites a Markush grouping of alternative limitations, defined by their function or desired result (e.g., reducing plaque inflammation, reducing blood cholesterol, etc.), ending with “and combinations thereof”, within an open group of alternatives (the preamble of claim 7 contains the transitional phrase “comprising”). As such, it is indefinite which alternatives, or combination of alternatives, are required to meet the limitation of the claims. Further, claim 7 is indefinite as it is unclear what other alternatives are intended to be encompassed by the claim.
When claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. Halliburton Energy Servs., Inc. v. M-I LLC, 514 F.3d 1244, 1255, 85 USPQ2d 1654, 1663 (Fed. Cir. 2008). See MPEP 2173.05(g).
Without reciting the particular structure, materials or steps that accomplish the function or achieve the result, all means or methods of resolving the problem may be encompassed by the claim. See Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353, 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc).
The terms “plaque inflammation, plaque calcification, serum lipid levels, and plaque stability” in claim 7 are relative terms which render the claim indefinite. The terms “plaque inflammation, plaque calcification, serum lipid levels, and plaque stability” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As the relative terms are not defined, the scope of biomarkers which need to be measured to assess atherosclerotic plaque inflammation, calcification, stability, and so on required to meet the limitations of the claims are indefinite.
Applicant may cancel claim 7 or amend claim 7 to define the terms plaque inflammation, plaque calcification, serum lipid levels, plaque stability, etc. to clearly define the scope of the atherosclerotic plaque inflammation, calcification, stability, and so on required to meet the limitations of the claims. Further Applicant may amend claim 7 to change the ending of the claim to “or combinations thereof” instead of “and combinations thereof” to overcome this rejection.
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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th 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.
Claim 1 recites a method for treating atherosclerosis comprising administration of a TNAP inhibitor. The limitations of claim 7 are not considered further limiting as it presumed that any TNAP inhibitor which meets the requires of claim 1, treating atherosclerosis, will also have the required properties to meet the limitations of claim 7. Further, the manner and degree to which the TNAP inhibitors are to be used to reduce plaque inflammation, reduce plaque calcification, etc. is not specified, therefore one of ordinary skill in the art cannot be sure how the claimed limitations are further limiting.
This method recites step of administering TNAP inhibitor but does not include steps for achieving claimed results/limitations of claim 7. As such it is presumed the solution to the problem presented in claim 7, lie in the TNAP inhibitor of claim 1 as no additional agent or process steps are claimed.
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 § 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 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 1-3 and 5-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/054056 A1 (Gahl et al.), in view of Goettsch (Goettsch, Claudia, et al. "TNAP as a therapeutic target for cardiovascular calcification: a discussion of its pleiotropic functions in the body." Cardiovascular research 118.1 (2022): 84-96. Published: 18 October 2020) and Dahl (Dahl, Russell, et al. "Discovery and validation of a series of aryl sulfonamides as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP)." Journal of medicinal chemistry 52.21 (2009): 6919-6925).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Gahl discloses a method of treating a disease or disorder characterized by medial vascular calcification in a subject, including atherosclerosis, comprising administering a pharmaceutical composition comprising a small molecule TNAP inhibitor. See paragraphs 64-71, claims 1 and 3 of Gahl and present claims 1, 3 and 5. Gahl teaches where TNAP is a member of the alkaline phosphatase (AP) genus and is expressed in bone, liver and kidney. See paragraph 8 of Gahl.
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Figure 1. TNAP inhibitor SBI-425.
Gahl discloses where the TNAP inhibitor includes SBI-425. See paragraphs 91-93 and claims 14-15. SBI-425 corresponds to a compound of present Formula I of claim 6 where Y1 is a bond, Y2 is -N(R6)-, L1 is a bond, L2 is a bond, X1 is =C(R2)-, X2 is =C(R3)-, R1 is alkoxy, R2 is hydrogen, R3 is hydrogen, R4 is halogen, R5 is hydrogen, R6 is hydrogen, A is -C(O)-N(R7)-R8, R7 is hydrogen and R8 is hydrogen. See present claims 6 and 18. Gahl discloses “In effect, contemplated herein are any agents that can inhibit tissue-nonspecific alkaline phosphatases (TNAPs)” in paragraph 93 and provides a non-exhaustive list of potential TNAP inhibitors suitable for use in the method of treating atherosclerosis. See also claims 16-17 of Gahl.
Gahl disclose where the pharmaceutical composition is administered to a subject via subcutaneous injection and intravenous injection. See paragraphs 110-111 of Gahl and present claim 8.
Regarding present claim 9, Gahl discloses the following in paragraph 122:
The at least one TNAP inhibitor can, in certain embodiments, be combined, conjugated, or coupled with or to carrier(s) within a composition, for example, to make administration easier or to improve delivery of the inhibitor. Exemplary carrier examples include, without limitation, small molecules, pharmaceutical drugs, fatty acids, detectable markers, conjugating tags, nanoparticles, and enzymes. Ideally, the carrier is pharmaceutically acceptable, i.e., not biologically or otherwise undesirable. Thus, the carrier does not have a significant undesirable biological effect or interact in a significantly deleterious fashion with the inhibitor and/or any other optional component of the pharmaceutical composition. Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995.
See present claim 9.
Gahl discloses where the disease or disorder associated with medial vascular calcification to be treated by a TNAP inhibitor also includes diabetes mellitus (I or II). See paragraphs 15 and 80 as well as claim 3 of Gahl. See present claims 10-11.
Gahl discloses where the TNAP inhibitor can be administered in combination with lipid-lowering agents such as Lipitor, or atorvastatin, for treating atherosclerosis or a symptom of atherosclerosis. See paragraphs 102-103 of Gahl and present claims 12-14.
Gahl discloses methods for measuring biomarkers in a biological sample obtained in an individual prior to administering the TNAP inhibitor. Gahl provides working examples demonstrating the administration of SBI-425 for the treatment of pseudoxanthoma elasticum (PXE) where ALPL (the gene encoding TNAP) and ENPP1 mRNA expression levels are measured. See paragraphs 157-158 and Figure 1D of Gahl and present claims 15 and 16. Gahl also discloses where the protein level of ALPL and ENPP1 proteins are assessed in Figure 1C. See present claim 17.
Gahl discloses where the TNAP inhibitor is administered in a dose range of about 5 to about 30 mg/kg/day in paragraph 100. See present claim 20.
Regarding claim 7, Gahl discloses administration of a TNAP inhibitor (or composition comprising the same) can reduce serum PTH without causing aortic calcification. See paragraph 78 of Gahl. Gahl also discloses measuring levels of determinants and/or risk factors such as low- density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in order to assess vascular calcification. See paragraph 75 of Gahl.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
Gahl does not disclose wherein treating atherosclerosis comprises preventing, arresting, or reducing the development of plaque calcifications, wherein administering the pharmaceutical composition comprising the therapeutically effective amount of the TNAP inhibitor prevents, arrests, or reduces the development of plaque calcifications.
Gahl does not disclose where the method of treating atherosclerosis further comprises reducing plaque inflammation, reducing plaque calcification, reducing plaque size, reducing blood cholesterol, inhibiting TNAP present in a liver, increasing plaque stability, and combinations thereof.
Gahl does not disclose where the TNAP inhibitor is MLS-0038949. See present claim 19.
Finding of prima facie obviousness --- rationale and motivation (See
MPEP § 2142-2143)
Dahl discloses MSI-0038949 (2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide; Compound 1) as a potent TNAP inhibitor with excellent selectivity over other alkaline phosphatases, favorable ADME profiles, acceptable aqueous solubility, and good plasma levels after subcutaneous dosing. See page 6923, left column, lines 12-18.
Dahl discloses the following regarding MSI-0038949 as a TNAP inhibitor and potential suitability for therapeutic treatment:
Compound 1 was also tested for its ability to inhibit the function of NPP1, a phosphodiesterase that also has phosphatase activity and regulates ePPi production in skeletal tissue, and PHOSPHO1, a phosphatase with specificity for phosphethanolamine and phosphocholine, also involved in skeletal mineralization. At their optimal alkaline pHs, inhibition was less than 9.5% for NPP1 and 7.4% for PHOSPHO1. Thus, TNAP inhibitor 1 was established as a drug-like and selective probe molecule, prompting further evaluation of its therapeutic potential as a systemically active TNAP inhibitor.
The in vitro profile of 1 suggested that this compound had the potential for further development because it had properties indicative of systemic availability. To evaluate the potential for systemic activity, the plasma levels of compound 1 were assessed following subcutaneous administration. Rats were dosed subcutaneously with compound 1at 4.13 mg/kg. At the 1 h time point, compound 1 showed plasma levels consistent with achieving therapeutic concentrations (Cmax = 1.5 μg/mL), indicating the potential for in vivo efficacy. In summary, these data indicate that compound 1 may find utility as an in vivo tool for elucidating the role of TNAP in vascular calcification in animal models.
See pg. 6921, left column, line 30 to pg. 6921, right column, line 15 of Dahl.
Goettsch teaches where the “consequences of atherosclerotic intimal plaque calcification are less clear, although it is virtually present in every adult” in pg. 85, left column, lines 15-16.
Goettsch discloses TNAP inhibition may not only impact systemic inflammation but also tissue inflammation in several diseases, since neutrophils are often the first cells to be recruited in inflamed tissues, e.g. in atherosclerotic plaques, where neutrophils are the first cells to enter and stimulate inflammation. See pg. 90, right column, first full paragraph.
Goettsch discloses several preclinical studies showed that TNAP inhibition strongly reduces vascular calcification (VC). See pg. 92, left column, penultimate paragraph.
Goettsch discloses where oral supplementation of 30 mg/kg/day SBI-425 on atherosclerotic plaque calcification in a mouse model of familial hypercholesterolemia led to decreased coronary calcium accumulation, and left ventricular hypertrophy, indicating that SBI-425 may inhibit intimal atherosclerosis plaque calcification in addition to inhibiting medial calcification. See page 89, right column, lines 6-17.
It would have been obvious for one of ordinary skill in the art to substitute the TNAP inhibitor SBI-425, which Gahl and Goettsch disclose in a method of treating atherosclerosis and reducing atherosclerotic plaque calcification, for MSI-0038949 which Dahl discloses as a potent TNAP inhibitor. A person of ordinary skill in the art would have a reasonable expectation of success towards treating atherosclerosis with MSI-0038949 as the Gahl method of treating atherosclerosis is provided as inclusive of all small molecules which inhibit TNAP and Dahl provides data demonstrating MSI-0038949 as a potent TNAP inhibitor.
Regarding claim 2, the prior art discloses where TNAP is critical for calcification and atherosclerotic plaques and where TNAP inhibitors reduce coronary calcification and thus can be used to prevent or reduce the development of plaque calcifications. As the present claim encompasses the prevention and reduction of the development of plaque calcifications, one practicing the method of treating atherosclerosis comprising administration of a TNAP as disclosed in the prior art, would also entail administration by a PHOSITA to a patient population embraced by the present claims, atherosclerosis patients having plaque calcifications. As the prior art discloses nearly every adult has atherosclerotic plaque calcification, there is a reasonable expectation of preventing, arresting or reducing in a patient population encompassed within the scope of the present claims.
Regarding claim 7, the prior discloses a method of treating atherosclerosis comprising administration of a TNAP inhibitor and further where TNAP inhibition is critical in reducing atherosclerotic plaque calcification, plaque inflammation and can also reduce serum levels associated with diseases such as atherosclerosis. Further, the prior art discloses where TNAP is present in the liver as well as methods of measuring LDL and HDL cholesterol levels to assess vascular calcification within the method of treating atherosclerosis.
Without reciting the particular structure, materials or steps that accomplish the function or achieve the result, all means or methods of resolving the problem may be encompassed by the claim. Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353, 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). See MPEP 2173.05(g). In the present situation, the present claim requires various additional results within the method of atherosclerosis; however, no additional steps or structures are provided for accomplishing the intended results.
Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). Granting a patent on the discovery of an unknown but inherent function "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991). See MPEP 2145, Section II. "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
As such it is presumed one of ordinary skill in the art which administers a TNAP inhibitor in a method of treating atherosclerosis as required in parent claim 1 will meet the limitations of reducing plaque inflammation, reducing plaque calcification, reducing plaque size, reducing blood cholesterol, inhibiting TNAP present in a liver, increasing plaque stability, and combinations thereof as required in present claim 7.
Therefore, the present claims are prima facie obvious in view of the prior art of Dahl, Gahl and Goettsch.
Conclusion
Claims 1-3 and 5-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QUINCY A MCKOY whose telephone number is (703)756-4598. The examiner can normally be reached Monday - Thursday 8:00 - 6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joseph McKane can be reached at 5712720699. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/QUINCY A. MCKOY/
Patent Examiner, Art Unit 1626
/KAMAL A SAEED/Primary Examiner, Art Unit 1626