DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-155 have been canceled.
Claims 156-191 are pending in the instant application.
Claims 156, 166, 179, and 187 are independent.
Applicant’s election of the invention of group I, drawn to methods of treating Moyamoya disease by administering ENPP1 polypeptides in the reply filed on November 24, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 179-191 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 24, 2025 as discussed above.
Claims 156-178 are under examination in this office action.
Information Disclosure Statement
The IDS forms received 9/5/2023, 5/20/2024, 7/10/2024, and 9/19/2025 are acknowledged and the references cited therein have been considered.
Claim Rejections - 35 USC § 112
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 171 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 171 depends directly from independent claim 166, and claim 166 recites administering an ENPP1 agent to a subject. Dependent claim 171 recites that the subject is administered an ENPP1 agent OR an ENPP3 agent. The independent claim does not recite ENPP3 and requires administration of ENPP1. As such by allowing administration of ENPP3 alone, claim 171 is broader in scope than the independent claim from which it depends.
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.
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 170 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 170 recites the limitation "the surgical intervention is .." in line 1 of the claim. There is insufficient antecedent basis for this limitation in the claim as the independent claim from which claim 170 directly depends (i.e. independent claim 166) does not recite any surgical intervention. As such there is no antecedent basis in the independent claim for the surgical intervention.
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 156-158 and 160-178 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant has claimed methods of treating patients having or at risk of developing moyamoya disease by administering an “ENNP1 agent”, wherein such administrations “inhibit or prevent” cerebral vascular occlusion or unwanted vascular smooth muscle cell proliferation. Page 30 of the instant specification defines “ENPP1 agent” as follows:
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Notably, “ENPP1 polypeptide” is defined on page 27 as encompassing biological sequence mutants as shown below:
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Thus, while an “ENPP1 agent” must have enzymatic activity it need not have any particular biological sequence, with instant claims 165 and 178 explicitly requiring the administration of variant sequences as part of the claimed methods.
To support such breadth, the application discloses SEQ ID NO:1, which is the human wild type sequence of ENPP1, as well as fusion proteins comprising the soluble extracellular domain of human ENPP1 in SEQ ID NOs:2-4 (see pages 50-53). Note that ENPP1 is a type II transmembrane domain and as such SEQ ID NO:1 is not reasonably soluble (see particularly the paragraph spanning pages 26 and 27 of the instant specification as well as the first full paragraph of page 137). Example 11 discloses a mouse model of moyamoya disease induced by surgery while prophetic example 12 asserts that administration of ENPP1 or ENPP1-Fc a week prior to surgery as disclosed in example 11 will prevent occlusion with similar results asserted to occur in human patients in example 18. Notably, no experimental data wherein mice (or humans) were administered ENPP1 before or after onset of moyamoya are disclosed in the instant specification. Notably, page 33 appears to indicate that “moyamoya disease” and “moyamoya syndrome” have the same clinical signs and are often not distinguished form one another in the medical literature:
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As discussed above, the specification defined “ENPP1 agent” as encompassing polypeptide mutants that maintain enzymatic activity and discloses no examples of making such mutants other than sequence truncations (i.e. making a transmembrane protein soluble). The specification attempts to point to other locations where such mutants can be located on page 27. Specifically, it is stated:
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Thus the specification attempt to incorporate by reference such mutant sequences, and given the lack of such mutants (other than simple truncations to remove the transmembrane and intracellular domains) it reasonably appears that such information is needed to make and use the full breadth of “ENPP1 agents”. However, as is set forth in MPEP 608.01(p) as well as 37 CFR 1.57,
(d) "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. "Essential material" is material that is necessary to:
(1) Provide a written description of the claimed 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 set forth the best mode contemplated by the inventor of carrying out the invention as required by 35 U.S.C. 112(a);
(2) Describe the claimed invention in terms that particularly point out and distinctly claim the invention as required by 35 U.S.C. 112(b); or
(3) Describe the structure, material, or acts that correspond to a claimed means or step for performing a specified function as required by 35 U.S.C. 112(f).
Note that a WIPO publication is not a US patent or a US patent application publication, and that guidance and direction concerning mutant ENPP1 sequences reasonably is needed to be able to make and use the full extent of that which has been presently claimed. Thus the instant specification does not reasonably teach artisans how to make and use the ENPP1 agents administered as part of the instant claimed methods in the absence of additional undue basic science research and experimentation.
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 (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.
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 156-178 are rejected under 35 U.S.C. 103 as being unpatentable over Uchikawa et al. in view of Quinn et al. (US 2014/0154774)
Uchikawa et al. disclose a patient having moyamoya syndrome, a progressive cerebrovascular disease characterized by stenosis of the terminal portion of the internal carotid artery and its main branches, in combination with brain calcification and stenosis of abdominal aorta and renal arteries (see entire document, particularly the abstract and Figures 1 and 2). They further report that calcification of the brain is also present in moyamoya disease including those having the RFN 213 genetic mutation (see particularly the first full paragraph of the left column of page 712). Such teachings differ from what is presently claimed in that the patient of Uchikawa et al. was not administered soluble ENPP1 to treat the clinical condition.
Quinn et al. disclose administration of fusion proteins comprising soluble human ENNP1 joined to immunoglobulin Fc domain to patients for the purpose of treating arterial blockages caused by calcification (see entire document, particularly the abstract and paragraphs [0005-0009] and [0039] and the enclosed sequence alignments). Such fusion proteins are disclosed as having heterologous moieties joined to the C terminal end of ENPP1 with and without linker sequences (see particularly paragraphs [0040-0048] and Figure 22B). Notably the soluble ENPP1 fusion proteins are disclosed as being enzymatically active and that this activity is needed for inhibiting calcification (see particularly paragraphs [0005] and [0039] as well as example V).
Therefore it would have been obvious to a person of ordinary skill in the art at the time of the invention to administer the ENPP1-Fc fusion proteins of Quinn et al. to the moyamoya patient of Uchikawa et al. Ordinary artisans would have been motivated to do so in order to reduce the calcification seen in the arteries of the moyamoya patient of Uchikawa et al.
Claims 156-178 are rejected under 35 U.S.C. 103 as being unpatentable over Uchikawa et al. in view of Braddock et al. (US 2015/0359858)
Uchikawa et al. disclose a patient having moyamoya syndrome, a progressive cerebrovascular disease characterized by stenosis of the terminal portion of the internal carotid artery and its main branches, in combination with brain calcification and stenosis of abdominal aorta and renal arteries (see entire document, particularly the abstract and Figures 1 and 2). They further report that calcification of the brain is also present in moyamoya disease including those having the RFN 213 genetic mutation (see particularly the first full paragraph of the left column of page 712). Such teachings differ from what is presently claimed in that the patient of Uchikawa et al. was not administered soluble ENPP1 to treat the clinical condition.
Braddock et al. disclose administration methods to treat pathological calcification conditions comprising administration of fusion proteins comprising soluble enzymatically active human ENNP1 joined to immunoglobulin Fc domain to patients (see entire document, particularly the abstract, paragraph [0012], and claims, particularly claim 4 as well as the enclosed sequence alignments). Notably the soluble ENPP1 fusion proteins are discloses as being enzymatically active and that this activity is needed for inhibiting calcification (see particularly paragraphs [0109-0112]).
Therefore it would have been obvious to a person of ordinary skill in the art at the time of the invention to administer the ENPP1-Fc fusion proteins of Braddock et al. to the moyamoya patient of Uchikawa et al. Ordinary artisans would have been motivated to do so in order to reduce the calcification seen in the arteries of the moyamoya patient of Uchikawa et al.
Claims 156-178 are rejected under 35 U.S.C. 103 as being unpatentable over Harel et al. in view of Quinn et al. (US 2014/0154774)
Harel et al. disclose an infant patient having moyamoya due to the R4010K mutation in RNF213, including bilateral stenosis of internal carotid arteries including calcification thereof (see entire document, particularly the abstract, Figure 2, and the left column of page 2743). The patient was surgical treated at ten months of age (see particularly the right column of page 2743). Such teachings differ from what is presently claimed in that the patient of Harel et al. was not administered soluble ENPP1 to treat the clinical condition.
Quinn et al. disclose administration of fusion proteins comprising soluble human ENNP1 joined to immunoglobulin Fc domain to patients for the purpose of treating arterial blockages caused by calcification (see entire document, particularly the abstract and paragraphs [0005-0009] and [0039] and the enclosed sequence alignments). Such fusion proteins are disclosed as having heterologous moieties joined to the C terminal end of ENPP1 with and without linker sequences (see particularly paragraphs [0040-0048] and Figure 22B). Notably the soluble ENPP1 fusion proteins are disclosed as being enzymatically active and that this activity is needed for inhibiting calcification (see particularly paragraphs [0005] and [0039] as well as example V).
Therefore it would have been obvious to a person of ordinary skill in the art at the time of the invention to administer the ENPP1-Fc fusion proteins of Quinn et al. to the moyamoya patient of Harel et al. Ordinary artisans would have been motivated to do so in order to reduce the calcification seen in the arteries of the moyamoya patient of harel et al.
Claims 156-178 are rejected under 35 U.S.C. 103 as being unpatentable over Harel et al. in view of Braddock et al. (US 2015/0359858)
Harel et al. disclose an infant patient having moyamoya due to the R4010K mutation in RNF213, including bilateral stenosis of internal carotid arteries including calcification thereof (see entire document, particularly the abstract, Figure 2, and the left column of page 2743). The patient was surgical treated at ten months of age (see particularly the right column of page 2743). Such teachings differ from what is presently claimed in that the patient of Harel et al. was not administered soluble ENPP1 to treat the clinical condition.
Braddock et al. disclose administration methods to treat pathological calcification conditions comprising administration of fusion proteins comprising soluble enzymatically active human ENNP1 joined to immunoglobulin Fc domain to patients (see entire document, particularly the abstract, paragraph [0012], and claims, particularly claim 4 as well as the enclosed sequence alignments). Notably the soluble ENPP1 fusion proteins are discloses as being enzymatically active and that this activity is needed for inhibiting calcification (see particularly paragraphs [0109-0112]).
Therefore it would have been obvious to a person of ordinary skill in the art at the time of the invention to administer the ENPP1-Fc fusion proteins of Braddock et al. to the moyamoya patient of Harel et al. Ordinary artisans would have been motivated to do so in order to reduce the calcification seen in the arteries of the moyamoya patient of Harel et al.
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641