DETAILED ACTION
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 .
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 because there are sequences in figures 13, 14, and 17, for example, that do not contain a SEQ ID NO.
A complete response to this office action must correct the defects cited above regarding compliance with the sequence rules and a response to the action on the merits which follows.
The aforementioned instance of failure to comply is not intended as an exhaustive list of all such potential failures to comply in the instant application. Applicants are encouraged to thoroughly review the application to ensure that the entire application is in full compliance with all sequence rules. This requirement will not be held in abeyance.
Drawings
The drawings filed on 6/17/24 are objected to because they contain sequences that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2), but each sequence does not contain a SEQ ID NO., as explained in the “Sequence Compliance” section above. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1, 2, 4-17, 20, and 23-30 are objected to because of the following informalities: Claim one recites “LPA” which is an abbreviation. Applicant is required to recite what the abbreviation stands for at the first recitation of the abbreviation (i.e. “apolipoprotein (a) (LPA)”. From a google search, LPA can have various meanings including “lysophosphatidic acid” or “lipoprotein(a)”. Appropriate correction is required. Claims 2, 4-17, 20, and 23-30 are objected to because they depend from claim 1 and do not obviate the objection.
Claim 5 is objected to because of the following informalities: Claim 5 recites “wherein the at least one duplex region consists of 17-25 or consecutive nucleotide base pairs”, which does not make sense. It appears that applicant inadvertently inserted the word “or”. Appropriate correction is required.
Claim 14 is objected to because of the following informalities: Claim 14 recites “according ot claim 13” instead of “according to claim 13”. Appropriate correction is required.
Claim 15 is objected to because of the following informalities: Claim 15 recites “a phosphorothioate linkages”, rather than “a phosphorothioate linkage” (not plural). Appropriate correction is required.
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 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 7 is dependent upon claim 1 and recites “wherein one or more nucleotides on the first and/or second strand are modified, to form modified nucleotides.” This does not further limit the base claim, which already requires all nucleotides of the first strand to be modified. 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.
Claims 14 and 15 are 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.
The language of claim 14 is not definite because the metes and bounds of the claim are not clear. Claim 14 recites “wherein Z is a nucleic acid according ot claim 13”, which is believed to be intended to recite “wherein Z is a nucleic acid according to claim 13”. The language “according to” does not set forth a clear and defined requirement. It is unclear whether Z is required to consist of the nucleic acid of claim 13, to comprise the nucleic acid of claim 13, or to be some other variation of the nucleic acid of 13. It is unclear what specifically is required by “according” to.
Claim 15 is rejected because it depends from claim 14 and does not obviate the rejection.
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, 4-17, 20, and 23-30 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is directed to a nucleic acid for inhibiting expression of LPA in a cell, comprising “at least one duplex region” that comprises at least “a portion” of a first strand and at least “a portion” of a second strand that is at least “partially complementary” to the first strand, wherein said first strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides differing by no more than three nucleotides from SEQ ID NO: 9, wherein all nucleotides of the first strand are modified with either a 2' O-methyl modification or 2' fluoro modification.
The claim encompasses an enormous possible genus of nucleic acids with differing structures that have not been adequately described by the specification. The specification discloses specific siRNAs targeting a specific LPA sequence, which is a species that is not representative of the entire claimed genus.
The instant claims encompass nucleic acids having two strands of any length (i.e. thousands of nucleotides), wherein each strand is not necessarily the same length (i.e. one that is two thousand nucleotides in length and one that is 15 nucleotides in length), wherein the two strands can have a duplex region of any length (i.e. 2 nt)(any portion of the first and second strand), wherein the duplex region can have any level of complementarity (i.e. 2 nt) (recited as at least partially complementary), wherein the first strand comprises 12 nucleotides of SEQ ID NO: 9 and any possible second strand as long as it has partial complementarity (i.e. 2 nt) with the first strand.
The specification does not adequately describe the structure required for the function.
The claims read upon varying configurations of compounds with different numbers of duplexes and varying length ranges. The specification does not adequately describe this genus of compounds.
The specification does not adequately describe the structure required for the agent to function by inhibiting expression of LPA as claimed.
Claim 29 requires for the pathology to be “one associated with elevated levels of Lp(a)-containing particles. The specification does not adequately describe which specific pathologies meet the limitation of having any type of association with elevated levels of Lp(a)-containing particles.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
With regards to siRNAs, to achieve the desired function, it appears that the structure is required to be of a shorter length than the claimed genus which has no length limitation. For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) (of record and cited on the IDS filed on 9/25/25) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
Claim 4 limits the length of one strand only by reciting that the first strand and/or the second strand are each from 17-35 nucleotides. The language reads upon the alternative (or) but then requires each, which is both, which is conflicting language. Claim 5 limits the length of one duplex region, but not the nucleic acid itself. Claim 13 requires for the first strand to comprise or consist of SEQ ID NO: 9 and recites an optional and therefore not required limitation for the second strand. The first strand can be thousands of nucleotides in length and comprise instant SEQ ID NO: 9. Claim 23 requires for the second strand to comprise at least 12 nucleotides of SEQ ID NO: 10, but the strand can be thousands of nucleotides in length. Claim 24 requires for the second strand to comprise SEQ ID NO: 10, but the strand can be thousands of nucleotides in length and comprise instant SEQ ID NO: 10.
The claims encompass an enormous possible genus of compounds that have different lengths and configurations and can have other duplex regions much longer than the region targeted to LPA.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for nucleic acids within the instant enormous genus that are inhibitory of the target as claimed. Thus, one skilled in the art would be lead to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claims 27-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of inhibiting LPA via delivery of a siRNA comprising instant SEQ ID NOs: 9 and 10, does not reasonably provide enablement for broad delivery of any compound of any length meeting the instant structural limitations and various numbers of duplexes and a predictable outcome of treatment of any disease, disorder, or syndrome; or reducing the risk of any pathology associated with elevated levels of Lp(a)-containing particles. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method of broad delivery of any nucleic acid having two strands of any length (i.e. thousands of nucleotides), wherein each strand is not necessarily the same length (i.e. one that is two thousand nucleotides in length and one that is 15 nucleotides in length), wherein the two strands can have a duplex region of any length (i.e. 2 nt)(any portion of the first and second strand), wherein the duplex region can have any level of complementarity (i.e. 2 nt) (recited as at least partially complementary), wherein the first strand comprises 12 nucleotides of SEQ ID NO: 9 and any possible second strand as long as it has partial complementarity (i.e. 2 nt) with the first strand and the predictable outcome of treatment of any disease, disorder, or syndrome; or reducing the risk of any pathology associated with elevated levels of Lp(a)-containing particles.
The specification does not draw an adequate nexus between delivery of the instant genus of compounds, or even delivery of any LPA specific siRNA, and the predictable outcome of the treatment of any possible disease, disorder, or syndrome, or reducing the risk of any pathology associated with elevated levels of Lp(a)-containing particles which clearly embraces an enormous genus of diseases, disorders, or syndromes that have not been shown to be reliant upon LPA alone.
The specification does not demonstrate treatment of even a single species of disease, disorder, or syndrome or reducing the risk of any pathology associated with elevated levels of Lp(a)-containing particles via delivery of any specific nucleic acid. The specification demonstrates LPA targeted siRNA with a resultant LPA inhibition.
The specification does not draw an adequate nexus between inhibition of LPA and the predictable treatment of any disease, disorder, or syndrome; or reducing the risk of any pathology associated with elevated levels of Lp(a)-containing particles.
Braddock (US 2011/0110886 A1) (of record and cited on the IDS filed on 9/25/25) teaches that [0007] ATX is an extracellular prometastatic enzyme and therefore an attractive molecular target for melanoma since inhibitory compounds can reach the target site without having to cross the cell membrane. LPA analogues are effective ATX inhibitors, and successfully inhibit tumor growth in animal models. Braddock is evidence that inhibition of LPA would not necessarily treat any possible disease. Inhibition or agonism of any particular target has different effects in different disease states.
It is noted that the claims are not even directed to delivery of specific agents that have shown to inhibit LPA, but even those that have been shown to effectively inhibit LPA would not result in each of the recited outcomes in a predictable manner.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating an enormous genus of diseases, disorders, and syndromes and reducing the risk of any pathology associated with elevated levels of Lp(a)-containing particles via inhibition of LPA alone encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of
the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27
USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of RNA in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful RNA interference. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the siRNA molecule in vivo, delivery of the siRNA molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
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 1, 2, 4-17, 20, and 23-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12,054,717 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US ‘717 B2 are directed to a method of treating a cardiovascular disease, disorder, or syndrome comprising administering a duplex of instant SEQ ID NOs: 9 and 10, which is a species that anticipates the instant genus. The product of the method of US ‘717 is a species that anticipates the instant product.
It is noted that there was a restriction in application 17/697,405 between the method of treatment and the method of reducing risk. However, the claims are considered to be obvious variations because they recite identical method steps. The patented method recites a step that anticipates the instantly recited method step. There is no bar for the instant rejection because the instant application is not a divisional application of 17/697,405.
Claims 1, 2, 4-17, 20, and 23-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,319,537 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US ‘537 B2 are directed to a product that anticipates the instant product. It would have been obvious to utilize the product in the instant methods because the methods are the intended use of the product.
There is no bar for the instant rejection because the instant application is not a divisional application of 16/763,458.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached on M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/ Primary Examiner, Art Unit 1636
Prosecution Insights