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
Status of Application, Amendments, and/or Claims
The Information Disclosure Statements (IDS) filed 5 September 2023, 8 October 2024, 26 August 2025, 28 October 2025, and 12 November 2025 have been entered. Applicant’s preliminary amendment of the claims filed 29 January 2024 has been entered.
Claims 1-73 are cancelled. Claims 74-103 have been added. Claims 74-103 are pending and under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see, for example, pages 37 and 93). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Objections
The following claims are objected to because of the informalities:
Independent claims 74-77 use acronyms without first defining what they represent in the independent claims (e.g., “ENPP1”, “ABCC6”). While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym.
In claims 74-77, the phrase “to thereby … or reduce vascular calcification in the subject” in claim 74 should be “to thereby … or reduce pathological calcification in the subject”; the phrase “to thereby ameliorate …” in claims 75-76 should be “to thereby treat or ameliorate …”; and the phrase “to thereby increase circulating PPi in the subject” in claim 77 should be “to thereby increase circulating PPi or increase pyrophosphatase activity in the subject”. Such that these phrases are consistent to the preambles.
In claims 82, 90, 96 and 101, the phrase “amino acid residues 99 (PSCAKE) to 925 (QED) of SEQ ID NO:1” should be “amino acid residues 99 to 925 of SEQ ID NO:1”.
In claim 83, 91, 97 and 102, the phrase “the amino acid sequence depicted in SEQ ID NO: 2 or 3 or 4 or 5” should be “the amino acid sequence depicted in SEQ ID NO: 2, 3, 4 or 5”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 74-81, 84-89, 92-95, 98-100 and 103 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 claims contain 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 instant claims are drawn to a method for preventing the progression of or reducing pathological calcification in a subject with ENPP1 deficiency, for treating or ameliorating one or more symptoms of ENPP1 deficiency or ABCC6 deficiency in a subject, or for increasing circulating pyrophosphate (PPi) or pyrophosphatase activity in a subject with ENPP1 deficiency or ABCC6 deficiency, said method comprising administering to the subject an ENPP1 agent at a dose of 0.2, 0.6, or 1.8 mg/kg of the subject.
The claims are broad and encompass the use of a genus of ENPP1 agents, however, the specification fails to provide adequate written description and evidence of possession of these agents. What Applicant has described in the specification are the full-length human ENPP1 protein set forth in SEQ ID NO: 1, a fragment thereof corresponding to amino acids 99-925 of SEQ ID NO: 1 (depicted in SEQ ID NO: 2), and fusion proteins thereof set forth in SEQ ID NOs: 3-5. The specification describes at page 40 that “An ENPP1 agent is an ENPP1 polypeptide. ENPP1 polypeptides disclosed herein include naturally occurring polypeptides of the ENPP1 family as well as any variants thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retain a biological activity.” However, except for the ENPP1 polypeptides comprising amino acids 99-925 of SEQ ID NO: 1, the specification does not teach the structural characteristics of the genus of the ENPP1 agents. The specification does not provide sufficient teachings regarding the correlation of structure to function, such as what structural characteristics are required for a polypeptide to exhibit the biological activity, or what changes can be made in a polypeptide without destroying the biological activity. It is well known in the art that even minor changes in sequence can result in major changes in function, especially if the minor sequence change occurs within an active site or alters the overall conformation of the molecule. For example, Wu et al. (Front. Endocrinol., 2025, Vol. 16:15663920) teaches that a single amino acid mutation (Y451C) affects the ENPP1 protein’s structure, reducing enzymatic activity by approximately 50% (see Abstract). Clearly, the effects of structural changes on an ENPP1 protein are unpredictable. In the absence of sufficient description of distinguishing identifying characteristics, the skilled artisan cannot envision the detailed structures of the encompassed genus of the ENPP1 agents that can be used in the treatment method as claimed.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making of the claimed product, or any combination thereof. In this case, there is no sufficient teachings regarding the structural characteristics of the genus, nor the correlation of structure to function. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must 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.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed structures of the encompassed genus of molecules, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that is part of the invention and reference to a method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, except for the ENPP1 polypeptides comprising amino acids 99-925 of SEQ ID NO: 1, but not the full scope of the claimed ENPP1 agents, are adequately described in the disclosure.
Claim Rejections - 35 USC § 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 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 of this title, 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 74-103 are rejected under 35 U.S.C. 103 as being unpatentable over Braddock et al. (US 2018/0057821 A1, Pub. Date: Mar. 1, 2018).
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 nonobviousness.
Braddock teaches a method of treating or preventing a disorder or disease in a subject where an increased activity or level of ectonucleotide pyrophosphate/phosphodiesterase-1 (NPP1) (also known as ENPP1) is desirable, said method comprising administering to the subject a therapeutically effective amount of a compound comprising (or consisting of) an NPP1 polypeptide or a fusion protein with a human IgG Fc domain [0100-0111] [0143]. Braddock teaches a NPP1 polypeptide which comprises the amino acid sequence of SEQ ID NO: 2 of the instant application (see sequence alignment attached). Braddock teaches that the disease or disorder is associated with pathological calcification or pathological ossification, e.g., GACI, IIAC, OPLL, hypophosphatemic rickets, osteoarthritis, and calcification of atherosclerotic plaques, PXE, hereditary and non-hereditary forms of osteoarthritis, ankylosing spondylitis, hardening of the arteries occurring with aging, or calciphylaxis resulting from end stage renal disease [0144] [0145], and the administering of the compound increases extracellular pyrophosphate (PPi) concentrations [0146]. Braddock teaches that the compound is administered subcutaneously [0149]. Braddock teaches that an effective dose range for a therapeutic compound of the invention is from about 0.01 and 50 mg/kg of body weight/per day, and one of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation [0179].
While Braddock does not specifically teach administering a dose of 0.2 mg/kg, 0.6 mg/kg, or 1.8 mg/kg, Braddock, however, teaches a dose range that contains the claimed doses, and Braddock indicates that one of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Given that the level of skill in this art is very high, and that optimizing parameters, such as the dosage of a therapeutic compound, is routine, modifying the dose range taught by Braddock to the claimed doses would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, with a reasonable expectation of success, absent evidence of unexpected results. As was found in In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), where the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 74-103 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-54 of copending Application No. 18/904,807 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. The claims of the ‘807 application are drawn to a method of reducing or preventing progression of a disease caused by lower levels of plasma PPi in a subject in need thereof, the method comprising: administering to the subject an ENPP1 agent at a dose of about 0.2 mg per kilogram of the subject, or about 0.6 mg per kilogram of the subject, or about 1.8 mg per kilogram of the subject, once a week, to increase circulating PPi levels thereby treating said disease in the subject. The claims of the ‘807 application anticipate the instant claims, and thus a nonstatutory double patenting rejection is proper.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
NO CLAIM IS ALLOWED.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/XIAOZHEN XIE/Primary Examiner, Art Unit 1674 December 13, 2025