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 .
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.
Claims 1-16 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 claims require administration to a subject a dsRNA agent, wherein the sense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from the “corresponding nucleotide sequence of SEQ ID NO: 2”.
The specification does not define the term “corresponding” or disclose the structural relationship required for the nucleotides from SEQ ID NO: 1 to correspond to SEQ ID NO: 2. The nucleotides could correspond by being located at the same position in the target or they could correspond by being the same type of nucleotide or they could correspond by complementarity. Therefore, the metes and bounds of the claims are not definite.
For purposes of the instant examination, the claims are interpreted as requiring administration to a subject a dsRNA agent, wherein the sense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides that are complementary to the same region of the sense strand.
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 1-30 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.
The claims are directed to a method of treating a subject having “a disorder that would benefit from reduction in xanthine dehydrogenase (XDH) expression”; wherein the disorder is “an XDH-associated disease”; further comprising administering to the subject an additional therapeutic “agent for the treatment of an XDH-associated disease”.
The specification does not adequately describe the genus of disorders that would benefit from reduction in xanthine dehydrogenase (XDH) expression; or the genus of diseases that are associated to XDH in any manner. Without further description of the genus, one would not be able to readily envision which diseases or disorders are necessarily included or excluded from the recited genus.
Additionally, the specification does not adequately describe the genus of agents that are for the treatment of any disease with any association to XDH. The specification does not adequately describe the structure required for the recited function. The specification discloses specific XDH siRNAs, which are not representative of the entire claimed genus.
The specification does not describe the instant genus of dsRNA agents of any length wherein the sense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2).
The species of the specification are not representative of the entire claimed genus. The structure recited encompasses a large genus of dsRNAs that would not likely have the function of inhibiting the expression of XDH. The dsRNA agent can be very long (i.e. 1,000 nucleotides) wherein the sense strand comprises 16 contiguous nucleotides of nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 19 contiguous nucleotides from a nucleotide sequence that corresponds in SEQ ID NO: 2. The species disclosed in the specification of a single siRNA targeting the instant region that comprises SEQ ID NOs: 135 and 494 is not representative of the entire claimed genus.
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 claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being dsRNA agents of any length that comprise 16 contiguous nucleotides of nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 19 contiguous nucleotides from a nucleotide sequence that corresponds in SEQ ID NO: 2 and function by inhibiting XDH; disorders that would benefit from reduction in xanthine dehydrogenase (XDH) expression; diseases that are associated to XDH in any manner; and agents that are for the treatment of any disease with any association to XDH.
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.
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. With respect to siRNAs, as single species of RNAi agents, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) 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).
The claims encompass very long dsRNA, for example, that can trigger RNAi. Such dsRNA with a sense strand with 16 contiguous nucleotides of nucleotides 2701-2721 of instant SEQ ID NO: 1 and the antisense strand comprises at least 19 contiguous nucleotides from a nucleotide sequence that corresponds in SEQ ID NO: 2 would not likely function as claimed. For example, Parrish et al. (Molecular Cell, Vol. 6, 1077–1087, November, 2000) teach that sequences of 1000 bp trigger RNAi (page 1078).
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 RNAi agents within the instant enormous genus that are inhibitory of the target as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claims 1-30 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 XDH in the liver via subcutaneous injection of a siRNA comprising SEQ ID NOs: 135 (sense strand) and 494 (antisense strand) (AD-1136091), does not reasonably provide enablement for the broad systemic delivery of any dsRNA of any length wherein the sense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2 and the predictable outcome of treating a subject having any disorder that would benefit from reduction in xanthine dehydrogenase (XDH) expression; wherein the disorder is a disease associated in any way to XDH. 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 claims are directed to a method of treating a subject having “a disorder that would benefit from reduction in xanthine dehydrogenase (XDH) expression”; wherein the disorder is “an XDH-associated disease”; further comprising administering to the subject an additional therapeutic “agent for the treatment of an XDH-associated disease” via delivery via any means of any dsRNA of any length wherein the sense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2.
The specification demonstrates in vivo delivery via subcutaneous injection to Cynomolgus monkeys of 11 specific XDH specific siRNAs (Example 4) with resultant varying levels of XDH inhibition (page 209, Figures 2 and 3). The specification does not demonstrate treatment of even a single species of diseases that would benefit from the reduction in XDH expression. It is noted that AD-1136091, the siRNA that targets the instantly recited region, resulted in the highest level of inhibition from the 11 siRNAs tested.
With regards to XDH inhibition in vivo, the specification demonstrates XDH inhibition via subcutaneous injection of a specific siRNA targeting the instantly recited region, which is not demonstrative of broad systemic delivery of any dsRNA of any length wherein the sense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2 and the predictable outcome of treating a subject having any disorder that would benefit from reduction in xanthine dehydrogenase (XDH) expression; wherein the disorder is a disease associated in any way to XDH.
The claims are not limited to the specific siRNA AD-1136091, but rather dsRNA agents of any length wherein the sense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1 and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2.
It is known in the field of siRNA design that such lack of specificity would not be enabled. For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) 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).
Even with regards to the specific siRNA AD-1136091, the specification does not draw an adequate nexus between broad systemic delivery of the siRNA and the predictable outcome of treating a subject having any disorder that would benefit from reduction in xanthine dehydrogenase (XDH) expression; wherein the disorder is a disease associated in any way to XDH. Applicant has not drawn an adequate nexus between inhibition of XDH alone and the predictable outcome of treating any specific disease or disorder. Even with those that may benefit from the reduction of XDH or be associated in some manner to XDH, each different disorder/disease would require varying levels of XDH inhibition for treatment; and each of the different diseases/disorders would require successful delivery to a different region of the body.
The specification does not draw an adequate nexus between broad systemic delivery of the instant agent and the predictable outcome of treating hyperuricemia or gout, the species of instant claims 3, 4, 23, and 24).
The references cited herein illustrate the state of the art for therapeutic in vivo applications using dsRNA.
Fujita et al. (Int. J. Mol. Sci. 2015, 16, 5254-5270) teach that two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications (page 5254). Fujita et al. teach that the success of an RNAi-based therapy in clinical trials rests on careful selection of target genes and miRNAs. Moreover, we suggest that a delivery route, sophisticated delivery carriers, chemical modification, and modified RNAi platforms are needed to enhance RNAi effects in cancer cells (pages 5262-5263).
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art for therapeutic in vivo applications. 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 any disorder that would benefit from reduction in xanthine dehydrogenase (XDH) expression; wherein the disorder is a disease associated in any way to XDH encompassing in vivo therapeutic 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 the dsRNA in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful RNA interference and treatment effects. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the dsRNA molecule in vivo, delivery of the dsRNA 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)).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-15 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Fitzgerald et al. (US 2018/0216114 A1).
Fitzgerald et al. teach methods of treating subjects having an XDH-associated disease comprising delivery of double stranded RNAi agents targeting XDH (abstract).
Fitzgerald et al. teaches a siRNA (AD-71809 A-144171) wherein each strand is 19 nucleotides in length and the sense strand comprises nucleotides 2705-2723 of GenBank NM_000379.3 (instant SEQ ID NO: 1) and the antisense strand is the complement thereof. The siRNA or Fitzgerald et al. therefore targets an overlapping region to the instantly claimed region (nucleotides 2701-2721 of SEQ ID NO: 1). The sense strand of the siRNA of Fitzgerald et al. comprises 17 contiguous nucleotides of nucleotides 2701-2721 of instant SEQ ID NO: 1 at positions 2705-2721 and therefore meets the instant limitation of comprising at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1. The antisense strand of the siRNA of Fitzgerald et al. is the 100% complement of the sense strand and therefore comprises at least 19 contiguous nucleotides from the “corresponding” nucleotide sequence of SEQ ID NO: 2 (see page 72 of Fitzgerald et al.)(instant claim 1).
Fitzgerald et al. teach: [0057] Accordingly, the present invention also provides methods for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of an XDH gene, e.g., an XDH-associated disease, such as gout, using iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of an XDH gene (instant claims 1, 2, and 4).
Fitzgerald et al. teach: [0019] In some embodiments, all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification (instant claim 1). In one embodiment, the modified nucleotides are independently selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxly-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. In another embodiment, the modified nucleotides comprise a short sequence of 3′-terminal deoxy-thymine nucleotides (dT), e.g., 1, 2, or 3 3′-terminal deoxy-thymine nucleotides (dT). In one embodiment, the modified nucleotides comprise two 3′-terminal deoxy-thymine nucleotides (dT) (instant claims 1 and 9).
Fitzgerald et al. teach: [0031] In an aspect, the invention provides a double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a XDH gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, respectively, wherein substantially all of the nucleotides of the sense strand comprise a nucleotide modification selected from a 2′-O-methyl modification and a 2′-fluoro modification, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus (instant claim 1), wherein substantially all of the nucleotides of the antisense strand comprise a nucleotide modification selected from a 2′-O-methyl modification and a 2′-fluoro modification, wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus (instant claim 1), and wherein the sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus (instant claim 1).
Therefore, Fitzgerald et al. teach each of the requirements of instant claim 1.
Fitzgerald et al. teach: [0130] The present invention provides iRNAs which inhibit the expression of an XDH gene. In preferred embodiments, the iRNA is a double stranded ribonucleic acid (dsRNA) molecule for inhibiting the expression of an XDH gene in a cell, such as a cell within a subject, e.g., a mammal, such as a human having an XDH-associated disease, e.g., hyperuricemia, gout (instant claims 3-5).
Fitzgerald et al. teach: [0050] In various embodiments, the dsRNA agent is administered at a dose of about 0.01 mg/kg to about 10 mg/kg or about 0.5 mg/kg to about 50 mg/kg. In some embodiments, the dsRNA agent is administered at a dose of about 10 mg/kg to about 30 mg/kg. In certain embodiments, the dsRNA agent is administered at a dose selected from 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, and 30 mg/kg. In certain embodiments, the dsRNA agent is administered about once per week, once per month, once every other two months, or once a quarter (i.e., once every three months) at a dose of about 0.1 mg/kg to about 5.0 mg/kg (instant claim 6).
Fitzgerald et al. teach: [0359] The present invention also includes pharmaceutical compositions and formulations which include the iRNAs of the invention. In one embodiment, provided herein are pharmaceutical compositions containing an iRNA, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the iRNA are useful for treating a disease or disorder associated with the expression or activity of an XDH gene. Such pharmaceutical compositions are formulated based on the mode of delivery. One example is compositions that are formulated for systemic administration via parenteral delivery, e.g., by subcutaneous (SC) (instant claim 7).
Fitzgerald et al. teach: [0455] The compositions of the present invention can additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions can contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, (instant claim 8).
Fitzgerald et al. teach that each strand is 19-25 nucleotides in length [0173] (instant claim 10).
Fitzgerald et al. teach: [0024] In many embodiments, the dsRNA agent further comprises a ligand. The ligand can be conjugated to the 3′ end of the sense strand of the dsRNA agent. The ligand can be an N-acetylgalactosamine (GalNAc) derivative including, but not limited to the structure identical to the structure of instant claim 14 (instant claims 11-14).
Fitzgerald et al. teach: [0026] In some embodiments, the dsRNA agents of the invention comprise a plurality, e.g., 2, 3, 4, 5, or 6, of GalNAc, each independently attached to a plurality of nucleotides of the dsRNA agent through a plurality of monovalent linkers (instant claims 13).
Fitzgerald et al. teach: [0027] An exemplary dsRNA agent conjugated to the ligand that is identical to the structure of instant claim 15 and, wherein X is O or S. In one embodiment, the X is O (instant claims 15
Therefore, the claims are anticipated by Fitzgerald et al.
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.
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 1-30 are rejected under 35 U.S.C. 103 as being unpatentable over Fitzgerald et al. (US 2018/0216114 A1).
Fitzgerald et al. teach methods of treating subjects having an XDH-associated disease comprising delivery of double stranded RNAi agents targeting XDH (abstract).
Fitzgerald et al. teaches a siRNA (AD-71809 A-144171) wherein each strand is 19 nucleotides in length and the sense strand comprises nucleotides 2705-2723 of GenBank NM_000379.3 (instant SEQ ID NO: 1) and the antisense strand is the complement thereof. The siRNA or Fitzgerald et al. therefore targets an overlapping region to the instantly claimed region (nucleotides 2701-2721 of SEQ ID NO: 1). The sense strand of the siRNA of Fitzgerald et al. comprises 17 contiguous nucleotides of nucleotides 2701-2721 of instant SEQ ID NO: 1 at positions 2705-2721 and therefore meets the instant limitation of comprising at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2701-2721 of SEQ ID NO: 1. The antisense strand of the siRNA of Fitzgerald et al. is the 100% complement of the sense strand and therefore comprises at least 19 contiguous nucleotides from the “corresponding” nucleotide sequence of SEQ ID NO: 2 (see page 72 of Fitzgerald et al.)(instant claim 1).
Fitzgerald et al. teach: [0057] Accordingly, the present invention also provides methods for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of an XDH gene, e.g., an XDH-associated disease, such as gout, using iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of an XDH gene (instant claims 1, 2, 4, 21, 22, and 24).
Fitzgerald et al. teach: [0019] In some embodiments, all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification (instant claim 1). In one embodiment, the modified nucleotides are independently selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxly-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. In another embodiment, the modified nucleotides comprise a short sequence of 3′-terminal deoxy-thymine nucleotides (dT), e.g., 1, 2, or 3 3′-terminal deoxy-thymine nucleotides (dT). In one embodiment, the modified nucleotides comprise two 3′-terminal deoxy-thymine nucleotides (dT) (instant claims 1 and 9).
Fitzgerald et al. teach: [0031] In an aspect, the invention provides a double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a XDH gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, respectively, wherein substantially all of the nucleotides of the sense strand comprise a nucleotide modification selected from a 2′-O-methyl modification and a 2′-fluoro modification, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus (instant claim 1), wherein substantially all of the nucleotides of the antisense strand comprise a nucleotide modification selected from a 2′-O-methyl modification and a 2′-fluoro modification, wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus (instant claim 1), and wherein the sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus (instant claim 1).
Therefore, Fitzgerald et al. teach each of the requirements of instant claim 1.
Fitzgerald et al. teach: [0130] The present invention provides iRNAs which inhibit the expression of an XDH gene. In preferred embodiments, the iRNA is a double stranded ribonucleic acid (dsRNA) molecule for inhibiting the expression of an XDH gene in a cell, such as a cell within a subject, e.g., a mammal, such as a human having an XDH-associated disease, e.g., hyperuricemia, gout (instant claims 3-5 and 22-25).
Fitzgerald et al. teach: [0050] In various embodiments, the dsRNA agent is administered at a dose of about 0.01 mg/kg to about 10 mg/kg or about 0.5 mg/kg to about 50 mg/kg. In some embodiments, the dsRNA agent is administered at a dose of about 10 mg/kg to about 30 mg/kg. In certain embodiments, the dsRNA agent is administered at a dose selected from 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, and 30 mg/kg. In certain embodiments, the dsRNA agent is administered about once per week, once per month, once every other two months, or once a quarter (i.e., once every three months) at a dose of about 0.1 mg/kg to about 5.0 mg/kg (instant claims 6 and 26).
Fitzgerald et al. teach: [0359] The present invention also includes pharmaceutical compositions and formulations which include the iRNAs of the invention. In one embodiment, provided herein are pharmaceutical compositions containing an iRNA, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the iRNA are useful for treating a disease or disorder associated with the expression or activity of an XDH gene. Such pharmaceutical compositions are formulated based on the mode of delivery. One example is compositions that are formulated for systemic administration via parenteral delivery, e.g., by subcutaneous (SC) (instant claims 7, 27, and 30).
Fitzgerald et al. teach: [0455] The compositions of the present invention can additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions can contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, (instant claims 8 and 28).
Fitzgerald et al. teach that each strand is 19-25 nucleotides in length [0173] (instant claim 10).
Fitzgerald et al. teach: [0024] In many embodiments, the dsRNA agent further comprises a ligand. The ligand can be conjugated to the 3′ end of the sense strand of the dsRNA agent. The ligand can be an N-acetylgalactosamine (GalNAc) derivative including, but not limited to the structure identical to the structure of instant claim 14 (instant claims 11-14 and 19).
Fitzgerald et al. teach: [0026] In some embodiments, the dsRNA agents of the invention comprise a plurality, e.g., 2, 3, 4, 5, or 6, of GalNAc, each independently attached to a plurality of nucleotides of the dsRNA agent through a plurality of monovalent linkers (instant claims 13).
Fitzgerald et al. teach: [0027] An exemplary dsRNA agent conjugated to the ligand that is identical to the structure of instant claim 15 and, wherein X is O or S. In one embodiment, the X is O (instant claims 15, 20, and 21).
Fitzgerald et al. does not teach that the antisense strand comprises instant SEQ ID NO: 494 and the sense strand comprises instant 135 (instant claims 16 and 17).
However, given that Fitzgerald et al. teach a siRNA targeted to the same region of the same target sequence, extending each strand of the siRNA that is 19 nt in length of Fitzgerald et al. to 25 nucleotides, which is within the 19-25 nucleotide size range taught by Fitzgerald et al., would result in an siRNA comprising instant SEQ ID NOs: 135 and 494. Designing the siRNA of Fitzgerald et al. at any length in the size ranges for siRNAs taught by Fitzgerald et al. is considered to be a matter of routine design (instant claims 16, 27, and 29).
Regarding instant claim 18, the placement of phosphorothioates is identical to that taught by Fitzgerald et al. as set forth above.
Regarding the modification pattern of instant claims 18 and 21, Fitzgerald et al. teach alternating 2’-O-methyl and 2’-F modifications [0204] and teaches various modification patterns, wherein the patterns include varying quantities of the modifications at various regions of each strand (pages 19-24). Fitzgerald et al. teaches modification patterns identical to the instant patterns in Table 4. Placement of each of the modifications is considered to be a routine parameter and the instant patterns are obvious in view of the patterns of Fitzgerald et al. (instant claims 18, 21, and 29).
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 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 11,326,166 B1. It is noted that the instant application is a continuation of application 17505732, US patent No. 11,326,166 B1. Although the claims at issue are not identical, they are not patentably distinct from each other because US ‘166 B1 recites a dsRNA wherein the sense strand comprises at least 16 (19 contiguous nucleotides differing by no more than 3) nucleotides from nucleotides 2691-2722 of SEQ ID NO: 1 and the antisense strand comprises SEQ ID NO: 494, which is identical to the instantly recited antisense strand (instant claims 16 and 17). The instant range of nucleotides 2701-2721 of SEQ ID NO: 1 falls completely within the patented range of nucleotides 2691-2722 of SEQ ID NO: 1. Additionally, claims 13-29 of US ‘166 B1 recite the identical compound as instantly claimed. It would have been obvious to utilize the patented compound in a method of treating a subject having a disorder that would benefit from the reduction in XDH because that is the intended use of the patented compound. Both applications have identical specifications to define the compound and its uses, doses, and modes of administration (instant claims 2-8 and 22-28). The claims of US ‘166 B1 recite the intended use of inhibition of XDH (claims 1, 12, 13, 26, 27, and 29). Both claim sets recite the same ligands, modifications, and pharmaceutical compositions.
The claims of US ‘166 B1 are as follows:
1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of xanthine dehydrogenase (XDH) in a cell, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of nucleotides 2691-2722 of SEQ ID NO: 1, and the antisense strand comprises a nucleotide sequence selected from the group consisting of 5′-AAAUACTCUGAGAGAGAUCCUGG-3′(SEQ ID NO:485); 5′-AUAATACUCUGAGAGAGAUCCUG-3′(SEQ ID NO:486); 5′-AAUAAUACUCUGAGAGAGAUCCU-3′(SEQ ID NO:487); 5′-ACAUAAUACUCUGAGAGAGAUCC-3′(SEQ ID NO:488); 5′-ACCAUAAUACUCUGAGAGAGAUC-3′(SEQ ID NO:489); 5′-AUCCAUAAUACUCUGAGAGAGAU-3′(SEQ ID NO:490); 5′-AUUCCAUAAUACUCUGAGAGAGA-3′(SEQ ID NO:491); 5′-AGUUCCAUAAUACUCUGAGAGAG-3′(SEQ ID NO:492); 5′-ACGUUCCAUAAUACUCUGAGAGA-3′(SEQ ID NO:493); 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494); and 5′-AGCUCGUUCCAUAAUACUCUGAG-3′(SEQ ID NO:495), wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus, and wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus (instant claims 1, 16, and 17).
2. The dsRNA agent of claim 1, wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythimidine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, a nucleotide comprising a 5′-phosphate mimic, a nucleotide comprising a 2′-phosphate, a thermally destabilizing nucleotide, a glycol modified nucleotide (GNA), and a 2-O—(N-methylacetamide) modified nucleotide; and combinations thereof (instant claim 9).
3. The dsRNA agent of claim 1, wherein the sense strand and the antisense strand are each independently 19-25 nucleotides in length (instant claim 10).
4. The dsRNA agent of claim 1, wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.
5. The dsRNA agent of claim 1, further comprising a ligand (instant claims 11 and 19).
6. The dsRNA agent of claim 5, wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent (instant claim 12).
7. The dsRNA agent of claim 6, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative (instant claim 13).
8. The dsRNA agent of claim 7, wherein the ligand is ##STR00039## (instant claims 14 and 20).
9. The dsRNA agent of claim 8, wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic ##STR00040## and, wherein X is O or S (instant claims 15 and 21).
10. The dsRNA agent of claim 1, wherein the sense strand and the antisense strand comprise nucleotide sequences selected from the group consisting of 5′-AGGAUCUCUCUCAGAGUAUUU-3′(SEQ ID NO:126) and 5′-AAAUACTCUGAGAGAGAUCCUGG-3′(SEQ ID NO:485); 5′-GGAUCUCUCUCAGAGUAUUAU-3′(SEQ ID NO:127) and 5′-AUAATACUCUGAGAGAGAUCCUG-3′(SEQ ID NO:486); 5′-GAUCUCUCUCAGAGUAUUAUU-3′(SEQ ID NO:128) and 5′-AAUAAUACUCUGAGAGAGAUCCU-3′(SEQ ID NO:487); 5′-AUCUCUCUCAGAGUAUUAUGU-3′(SEQ ID NO:129) and 5′-ACAUAAUACUCUGAGAGAGAUCC-3′(SEQ ID NO:488); 5′-UCUCUCUCAGAGUAUUAUGGU-3′(SEQ ID NO:130) and 5′-ACCAUAAUACUCUGAGAGAGAUC-3′(SEQ ID NO:489); 5′-CUCUCUCAGAGUAUUAUGGAU-3′(SEQ ID NO:131) and 5′-AUCCAUAAUACUCUGAGAGAGAU-3′(SEQ ID NO:490); 5′-UCUCUCAGAGUAUUAUGGAAU-3′(SEQ ID NO:132) and 5′-AUUCCAUAAUACUCUGAGAGAGA-3′(SEQ ID NO:491); 5′-CUCUCAGAGUAUUAUGGAACU-3′(SEQ ID NO:133) and 5′-AGUUCCAUAAUACUCUGAGAGAG-3′(SEQ ID NO:492); 5′-UCUCAGAGUAUUAUGGAACGU-3′(SEQ ID NO:134) and 5′-ACGUUCCAUAAUACUCUGAGAGA-3′(SEQ ID NO:493); 5′-UCAGAGUAUUAUGGAACGAGU-3′(SEQ ID NO:135) and 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494); and 5′-CAGAGUAUUAUGGAACGAGCU-3′(SEQ ID NO:136) and 5′-AGCUCGUUCCAUAAUACUCUGAG-3′(SEQ ID NO:495) (instant claims 16 and 17).
11. The dsRNA agent of claim 10, wherein the sense strand and the antisense strand comprise nucleotide sequences selected from the group consisting of 5′-asgsgaucUfcUfCfUfcagaguauuu-3′(SEQ ID NO:844) and 5′-asAfsaudAc(Tgn)cugagaGfaGfauccusgsg-3′(SEQ ID NO:1203); 5′-gsgsaucuCfuCfUfCfagaguauuau-3′(SEQ ID NO:845) and 5′-asUfsaadTa(C2p)ucugagAfgAfgauccsusg-3 ‘(SEQ ID NO:1204); 5’-gsasucucUfcUfCfAfgaguauuauu-3′(SEQ ID NO:846) and 5′-asAfsuaaUfacucugaGfaGfagaucscsu-3 ‘(SEQ ID NO:1205); 5’-asuscucuCfuCfAfGfaguauuaugu-3′(SEQ ID NO:847) and 5′-asCfsauaAfuacucugAfgAfgagauscsc-3′(SEQ ID NO:1206); 5′-uscsucucUfcAfGfAfguauuauggu-3′(SEQ ID NO:848) and 5′-asCfscauAfauacucuGfaGfagagasusc-3 ‘(SEQ ID NO:1207); 5’-csuscucuCfaGfAfGfuauuauggau-3′(SEQ ID NO:849) and 5′-asUfsccaUfaauacucUfgAfgagagsasu-3′(SEQ ID NO:1208); 5′-uscsucucAfgAfGfUfauuauggaau-3′(SEQ ID NO:850) and 5′-asUfsuccAfuaauacuCfuGfagagasgsa-3′(SEQ ID NO:1209); 5′-csuscucaGfaGfUfAfuuauggaacu-3′(SEQ ID NO:851) and 5′-asGfsuudCc(Agn)uaauacUfcUfgagagsasg-3′(SEQ ID NO:1210); 5′-uscsucagAfgUfAfUfuauggaacgu-3′(SEQ ID NO:852); and 5′-asCfsguuCfcauaauaCfuCfugagasgsa-3′(SEQ ID NO:1211); 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212); and 5′-csasgaguAfuUfAfUfggaacgagcu-3′(SEQ ID NO:854) and 5′-asGfscucGfuuccauaAfuAfcucugsasg-3′(SEQ ID NO:1213); wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; dA is 2′-deoxyadenosine-3′-phosphate; (Tgn) is a thymidine-glycol nucleic acid (GNA)S-Isomer; dT is 2′-deoxythimidine-3′-phosphate; (C2p) is cytidine-2′-phosphate; and (Agn) is an adenosine-glycol nucleic acid (GNA)S-Isomer (instant claims 18 and 29).
12. A pharmaceutical composition for inhibiting expression of a gene encoding xanthine dehydrogenase (XDH) comprising the dsRNA agent of claim 1 (instant claim 30).
13. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of xanthine dehydrogenase (XDH) in a cell, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 19 contiguous nucleotides differ