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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 07/20/2026 is acknowledged. Claims 5,21 and 34 were cancelled. Claims1,6,22 and 23 were amended. Claims 1-4,6-20,22-33 and 35-39 are pending.
Applicant elected the species of an siRNA including a nucleotide sequence of SEQ ID NO: 1 which hybridizes to an oligonucleotide encoding MMP13 in the reply filed on 11/10/2025 and was treated as an election without traverse (MPEP § 818.01(a)).
Priority
This application claims benefit of 63/484,459 filed 02/10/2023.
Withdrawn Objections and Rejections
Applicant’s arguments and amendments, see page 8, filed 07/20/2026, with respect to the objection to the specification for containing an embedded hyperlink have been fully considered and are persuasive due to the amendment to paragraph 0155 of the specification deleting “http://”. The objection to the specification has been withdrawn.
Applicant’s arguments and amendments, see page 8, filed 07/20/2026, with respect to the objection to claims 21 and 23 have been fully considered and are persuasive as claim 21 has been canceled and claim 23 has been amended to recite the full names for the abbreviated proteins. The objection to claims 21 and 23 has been withdrawn.
Applicant’s arguments, see page 11, filed 07/20/2026, with respect to the 35 U.S.C. 102(a)(1) rejection of claims 1-7,10,11,15-19,21-23,25,26,28-33,35-37 and 39 as anticipated by Colazo et al. have been fully considered and are persuasive, as Colazo is not prior art under 102(a)(1) as the disclosure date for Colazo et al. is July 8, 2022, and the filing date of the non-provisional application is March 10, 2023 and therefore falls under the exception under 102(b)(1)(A) as the disclosure date is less than a year before the earliest effective filing date. Colazo is also a joint inventor. The 102(a)(1) rejection has been withdrawn.
Applicant’s arguments and amendments, see pages 12-13, filed 07/20/2026, with respect to the 35 U.S.C. 103 rejection of claims 1-8,10,11,13-19,21-23,25-30,32 and 35-37 as obvious over McSwiggen in view of Sarett et al.; claims 9 and 12 as obvious over McSwiggen in view of Sarett and further in view of Brys; claims 24 and 38 as obvious over McSwiggen in view of Sarett in view of Nannuru, Hassler et al. and Gangopadhyay et al.; claims 31 and 39 as obvious over McSwiggen in view of Sarett and futher in view of Manoharan; and claims 20,31,33,34,38 and 39 as obvious over McSwiggen in view of Sarett and further in view of Dolan have been fully considered and are persuasive. Claim 1 has been amended to incorporate limitations of canceled claim 34 which was rejected as obvious over McSwiggen in view of Sarett and further in view of Dolan (WO 2023034561, also cited by the Examiner as “Duvall et al.”) and Applicant has stated that WO 2023034561 is not prior art under 102(a)(2) because it falls under the exemption of 35 U.S.C. 102(b)(2)(C) as the instant application and WO 2023034561 are subject to an obligation of assignment to the same legal person, Vanderbilt University at the time of filing, and therefore WO 2023034561 is not prior art. Therefore, the above 103 rejections have been withdrawn since claim 1 has been amended to incorporate the limitations of claim 34 and WO 2023034561 does not qualify as prior art.
New Rejection Necessitated by Amendment
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 23 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 23 depends on amended claim 1 which was amended to recite “wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein”, and claim 23 recites “wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding matrix metallopeptidase 13 (MMP13), Cadherin-11, matrix metallopeptidase-1 (MMP1), transcription factor SOX-5 (SOX5), nerve growth factor (NGF), or mitogen-activated protein kinase-activated protein kinase 2 (MK2). Therefore, some of the proteins recited in claim 23, such as Cadherin-11, SOX5, NGF and MK2 are not extracellular matrix degrading proteins as required by amended claim 1, and therefore claim 23 does not include all of the limitations of the claim upon which it depends, and does not further limit the subject matter.
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.
Maintained Rejections-Modified based on Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description Rejection
Claims 1-4,6-20,22-33 and 35-39 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-4,11-20,25-39 encompass treating an inflammatory disease, wherein the inflammatory disease is a genus of arthritis, in any subject in need thereof, comprising administering to the subject by any route of administration an effective amount of a conjugate comprising a genus of siRNA’s capable of inhibiting expression of a genus of proteins associated with the inflammatory disease, wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein; a genus of lipophilic ligands capable of binding albumin, and a genus of linkers attaching the siRNA to the lipophilic ligand, the linker comprising any branching molecule attached to the siRNA and any hydrophilic spacer attaching the branching molecule to the lipophilic ligand, and wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage. Claim 2 recites multiple species for the route of administration. Claims 6-10 further limit the inflammatory disease which is arthritis to osteoarthritis, rheumatoid arthritis, inflammatory arthritis, multi-joint arthritis, gout and psoriatic arthritis, however still encompass any route of administration and administering a genus of siRNAs capable of inhibiting expression of a genus of proteins associated with the inflammatory disease and wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein. Claims 15-20,28-33 and 39 recite further details of the linker in the conjugate and the lipophilic ligand. Claims 22-23 recite species of extracellular matrix degrading proteins that the siRNA is capable of hybridizing to but also include other species (Cadherin-11, SOX5, NGF and MK2) that do not fall within the scope of extracellular matrix degrading proteins, and claim 24 recites species of siRNA sequences (SEQ ID NOs: 1,2,3,4 or a combination thereof).
Regarding the state of the art of diseases associated with inflammation, Chen et al. (Oncotarget 2018, Vol. 9, No. 6, pp. 7201-7218) teach inflammatory pathways impact the pathogenesis of a number of chronic diseases, and involve common inflammatory mediators and regulatory pathways. Inflammatory stimuli activate intracellular signaling pathways that then activate production of inflammatory mediators. Primary inflammatory stimuli, including microbial products and cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), mediate inflammation through interaction with the TLRs, IL-1 receptor (IL-1R), IL-6 receptor (IL-6R), and the TNF receptor (TNFR) [20]. Receptor activation triggers important intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathways (page 7205, “Activation of inflammatory Pathways”). Chen et al. teach chronic inflammation occurs when acute inflammatory mechanisms fail to eliminate tissue injury, and may lead to a host of diseases, such as cardiovascular diseases, atherosclerosis, type 2 diabetes, rheumatoid arthritis, and cancers, and acute and chronic inflammation mediated tissue injury is observed in many organ systems, including the heart, pancreas, liver, kidney, lung, brain, intestinal tract, and reproductive system (page 7209, right column).
Regarding the genus of siRNA sequences capable of inhibiting expression of a protein associated with an inflammatory disease, Lu et al. (Advances in Genetics, Vol. 54, 2005, “In Vivo Application of RNA Interference: From Functional Genomics to Therapeutics”, pages 117-142) teach adoption of siRNA for functional genomics looking for inhibition of genes that can generate therapeutic benefits reversing pathological effects, often caused by overexpression of those same genes. However, the approach clearly depends on the effectiveness of siRNA delivery to modulate, very selectively, the expression of specific genes and, as a result, to induce physiological or pharmacological effects. A key requirement is identification of an effective site in the target mRNA sequence for siRNA accessibility (page 122, top paragraph). Therefore, Lu et al. shows the importance and requirement of identifying an effective site in the target mRNA sequence for the siRNA.
McSwiggen et al. (US 20090099121, Published 16 April 2009), teach compounds, compositions, and methods for treatment of diseases and conditions that respond to modulation of matrix metalloproteinase 13 (MMP13) gene expression and/or activity, including short interfering nucleic acid (siNA) and short interfering RNA (siRNA) molecules capable of mediating RNA interference against MMP13 gene expression and are useful for treating diseases and conditions that respond to modulation of MMP13 gene expression in a subject such as inflammatory diseases, disorders or conditions, including rheumatoid arthritis and osteoarthritis (paragraph 0003,0135-0137).
The instant specification only discloses 4 sequences for the siRNA, SEQ ID NO: 1,2,3,4 or a combination thereof (paragraph 0062). Page 61 of the instant specification shows that SEQ ID NO: 1 is the antisense sequence and SEQ ID NO: 2 is the sense sequence for the siRNA targeting mouse MMP13, and SEQ ID NO: 3 is the antisense sequence and SEQ ID NO: 4 is the sense sequence for the siRNA targeting Guinea Pig MMP13 and shows the chemical modifications of these sequences:
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Example 9 discloses Mouse and Guinea Pig MMP13 siRNA sequence screening including screening seven candidate siRNA sequences targeting different sites of the murine MMP13 gene and 4 candidate siRNA sequences targeting different sites of the guinea pig MMP13 gene, and that lead sequences were made into a 19-mer and formulated with stabilization chemistry i.e., “zipper” (paragraph 00143). The specific sequences screened are not disclosed and this example does not disclose that the lead sequences are SEQ ID NOs: 1-4.
Example 9 discloses an in vivo therapeutic study of siMMP13<(EG18L)2 in a post-traumatic osteoarthritis (PTOA) mechanical loading mouse model (paragraph 00157), and in a Guinea pig anterior cruciate ligament model by intravenous administration (paragraph 00162). Results of the experiments are found on pages 56-57, and that the example conjugate, si<(EG18L)2 and the modified nucleotides aided properties of the siRNA including stability in synovial fluid and in-vitro carrier-mediated silencing (Fig. 1A,1B,1C,1D) and knockdown of murine MMP13 (Fig 1F) and binding to albumin in OA and RA human synovial fluid (Fig 1E) and that regular siRNA without lipophilic albumin-binding moieties did not have any appreciable MMP13 knockdown (Fig. 1F) or binding of albumin in human synovial fluid (Fig. 1E) (paragraph 00170).
The conjugate was assessed in vivo in different inflammatory disease models and demonstrated preferential accumulation, retention and silencing of a target gene in an injured joint model of PTOA as shown in Fig. 2A-2I, 3A-3G, 4A-4G and 5A-5H. The conjugate also accumulated and had activity in all joints in a mouse model of rheumatoid arthritis (Fig. 6A-6G, 7A-7D, 8A-8G, 9A-9E) and that in both models intravenous delivery of the siRNA conjugate yielded accumulation in the affected joint, and the conjugate showed effective silencing in a guinea pig anterior cruciate ligament transection model (Fig. 10A-10F) (paragraph 00171).
When designed against matrix metalloproteinase 13 (MMP13), the siRNA conjugate robustly silenced MMP13 expression in the joints. In both the PTOA and RA models, silencing of MMP13 by systemic, intra-venous, treatment provided significant therapeutic benefits in terms of reducing joint inflammation, reducing cartilage loss, reducing synovial hyperplasia, maintaining bone homeostasis and reducing joint pressure sensitivity (pain). In-vivo subcutaneous studies (FIG. 11A - FIG. 11 C) show useful delivery and activity of siMMP13<(EG18L)2 at high doses and/or with the use of excipients. In-vivo local, intra-articular studies also show useful delivery, retention, and activity of siMMP 13<(EG18L)2 (FIG. 12A - FIG. 12F).
Therefore, the specification discloses methods of treating osteoarthritis, rheumatoid arthritis, post-traumatic osteoarthritis in a subject comprising administering by local, intra-articular, and intravenous administration, the conjugate of the siRNA of SEQ ID NOs: 1,2,3,4 (having the specific chemical modifications disclosed by these sequences described above) or combination thereof which targets mouse or guinea pig MMP13 conjugated to (EG18L)2 results in treatment of osteoarthritis, rheumatoid arthritis. However, as explained above, the instant claims directed to encompass treating an inflammatory disease, wherein the inflammatory disease is a genus of arthritis, with any siRNA sequence that is capable of inhibiting expression of any protein associated with any inflammatory disease and wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein, which encompasses millions of possible sequences towards many target proteins, as well as encompassing many different structures of the lipophilic ligand, and linker of the conjugate, which only correspond in some undefined way to specifically instantly disclosed chemicals. The instant specification lacks chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above treatment method using the specifically disclosed chemical structures, the skilled artisan cannot envision the detailed chemical structure of the encompassed siRNA sequences and structures of the conjugate regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. It is noted that only 4 siRNA sequences that target mouse or guinea pig MMP13, and none targeting human MMP13 or any other species have been provided. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003). Therefore, the specification does not show the required structure-function correlation for the recited genus of siRNA sequences capable of inhibiting the expression of a genus of proteins associated with inflammatory diseases and wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein, and that is conjugated to a genus of lipophilic ligands and linkers comprising a branching molecule attached to the siRNA and hydrophilic spacer attaching the branching molecule to the lipophilic ligand, and has the recited function of treating an inflammatory disease which is a genus of arthritis in a subject.
Therefore, only the above chemically structurally defined chemicals, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
Response to Arguments
Applicant's arguments and amendments, filed 07/20/2026 have been fully considered but they are not persuasive.
Applicant argues on page 9 that the rejection is not applicable to the claims as amended and recites what the amended claims are directed to, and that the skilled artisan would readily appreciate the meaning of the genera “arthritis” and “Extracellular matrix degrading protein” as well as the species in this genera, and many of these species are described in the specification and dependent claims such as claims 6,7,22 and 23. Applicant argues that the Office’s citation of Lu et al. in the rejection does not reflect advances in the state of the art for siRNAs since 2005 which have provided further guidance for selection of the proper sites for RNA targeting, and cites Hofacker et al. stating the earlier rules for target selection resulted in inconsistent activity but further research provides additional guidance and tools.
This is not found persuasive. First, it does not appear that Applicant has provided a copy of the Hofacker et al. reference cited in the arguments. Regarding the claim amendments, while claim 1 was narrowed regarding the genus of inflammatory diseases being treated to limit to arthritis, this still encompasses a genus of arthritic inflammatory diseases, and while claim 1 was amended to recite the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein, this still encompasses a large genus of possible siRNA sequences that hybridize to an oligonucleotide encoding a genus of extracellular matrix degrading proteins AND result in the functions recited in the claims (treat a genus of arthritis in any subject). By Applicant citing the Hofacker et al. reference and that since 2005 additional guidance and tools regarding target selection are provided, this does not help provide written description and pertains more to enablement regarding being able to make and use the invention.
See MPEP 2163 II.A.3. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
Therefore, Written Description for genus claims requires what core structure is required to achieve the recited functions in the claims and a structure-function correlation and in this case, the specification and state of the art does not show the required structure-function correlation for the recited genus of siRNA sequences capable of inhibiting the expression of a genus of proteins associated with inflammatory diseases and wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein, and that is conjugated to a genus of lipophilic ligands and linkers comprising a branching molecule attached to the siRNA and hydrophilic spacer attaching the branching molecule to the lipophilic ligand, and has the recited function of treating an inflammatory disease which is a genus of arthritis in a subject.
Applicant argues on page 9 that regarding claim 22, which as amended now recites the extracellular matrix degrading protein is MMP13, that the Office cites McSwiggen for setting forth connection between modulation of MMP13 and treatment of inflammatory disease such as rheumatoid arthritis and osteoarthritis, and notes that some of the instant applications examples are directed to specific siRNA for MMP13 sequences in a mouse or guinea pig model and because MMP13 sequence is highly conserved in e.g., humans, Applicant maintains that at a minimum the mouse and guinea pig results for MMP13 would provide direction to siRNA for this and other similarly conserved targets.
This is not found persuasive. See the rejection above which cites In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. This is applicable to the instant situation as a genus of siRNAs that bind to MMP13 is recited, and the specification only shows siRNA sequences for mouse and guinea pig. However, the instant claims also are directed to a method of using the siRNA to achieve a specific function (treating a genus of arthritic diseases) and therefore, even for claim 22, there is still not sufficient written description for the genus of siRNA sequences that hybridize to MMP13 and which are conjugated to the recited lipophilic ligand and linker and which result in treating a genus of arthritic diseases.
For these reasons, the written description rejection is maintained for all claims.
Claim Rejections-Scope of Enablement
Claims 1-4,6-20,22-33 and 35-39 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 treating osteoarthritis, rheumatoid arthritis or post-traumatic osteoarthritis in a subject in need thereof, comprising administering by local, intra-articular, and intravenous administration, the conjugate comprising the siRNA of instant SEQ ID NOs: 1,2,3 or 4 or a combination thereof (having the specific chemical modifications disclosed by these sequences described above) which targets mouse or guinea pig MMP13 conjugated to (EG18L)2 , does not reasonably provide enablement for a method of treating a genus of inflammatory diseases which are arthritis in a subject in need thereof, comprising administering by a genus of routes of administration, an effective amount of a conjugate comprising a genus of siRNA’s capable of inhibiting expression of a genus of proteins associated with the genus of inflammatory diseases and wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding a genus of extracellular matrix degrading protein; a lipophilic ligand capable of binding albumin; and a linker comprising a branching molecule attached to the siRNA and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The Breadth of the Claims and The Nature of the Invention
Claims 1-4,11-20,25-39 encompass treating an inflammatory disease, wherein the inflammatory disease is a genus of arthritis, in any subject in need thereof, comprising administering to the subject by any route of administration an effective amount of a conjugate comprising a genus of siRNA’s capable of inhibiting expression of a genus of proteins associated with the inflammatory disease, wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein; a genus of lipophilic ligands capable of binding albumin, and a genus of linkers attaching the siRNA to the lipophilic ligand, the linker comprising any branching molecule attached to the siRNA and any hydrophilic spacer attaching the branching molecule to the lipophilic ligand, and wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage. Claim 2 recites multiple species for the route of administration. Claims 6-10 further limit the inflammatory disease which is arthritis to osteoarthritis, rheumatoid arthritis, inflammatory arthritis, multi-joint arthritis, gout and psoriatic arthritis, however still encompass any route of administration and administering a genus of siRNAs capable of inhibiting expression of a genus of proteins associated with the inflammatory disease and wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein. Claims 15-20,28-33 and 39 recite further details of the linker in the conjugate and the lipophilic ligand. Claims 22-23 recite species of extracellular matrix degrading proteins that the siRNA is capable of hybridizing to but also include other species (Cadherin-11, SOX5, NGF and MK2) that do not fall within the scope of extracellular matrix degrading proteins, and claim 24 recites species of siRNA sequences (SEQ ID NOs: 1,2,3,4 or a combination thereof).
The State of the Prior Art
Regarding the state of the art of diseases associated with inflammation, Chen et al. (Oncotarget 2018, Vol. 9, No. 6, pp. 7201-7218) teach inflammatory pathways impact the pathogenesis of a number of chronic diseases, and involve common inflammatory mediators and regulatory pathways. Inflammatory stimuli activate intracellular signaling pathways that then activate production of inflammatory mediators. Primary inflammatory stimuli, including microbial products and cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), mediate inflammation through interaction with the TLRs, IL-1 receptor (IL-1R), IL-6 receptor (IL-6R), and the TNF receptor (TNFR) [20]. Receptor activation triggers important intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathways (page 7205, “Activation of inflammatory Pathways”). Chen et al. teach chronic inflammation occurs when acute inflammatory mechanisms fail to eliminate tissue injury, and may lead to a host of diseases, such as cardiovascular diseases, atherosclerosis, type 2 diabetes, rheumatoid arthritis, and cancers, and acute and chronic inflammation mediated tissue injury is observed in many organ systems, including the heart, pancreas, liver, kidney, lung, brain, intestinal tract, and reproductive system (page 7209, right column).
Regarding the genus of siRNA sequences capable of inhibiting expression of a protein associated with an inflammatory disease, Lu et al. (Advances in Genetics, Vol. 54, 2005, “In Vivo Application of RNA Interference: From Functional Genomics to Therapeutics”, pages 117-142) teach adoption of siRNA for functional genomics looking for inhibition of genes that can generate therapeutic benefits reversing pathological effects, often caused by overexpression of those same genes. However, the approach clearly depends on the effectiveness of siRNA delivery to modulate, very selectively, the expression of specific genes and, as a result, to induce physiological or pharmacological effects. A key requirement is identification of an effective site in the target mRNA sequence for siRNA accessibility (page 122, top paragraph). Therefore, Lu et al. shows the importance and requirement of identifying an effective site in the target mRNA sequence for the siRNA.
McSwiggen et al. (US 20090099121, Published 16 April 2009), teach compounds, compositions, and methods for treatment of diseases and conditions that respond to modulation of matrix metalloproteinase 13 (MMP13) gene expression and/or activity, including short interfering nucleic acid (siNA) and short interfering RNA (siRNA) molecules capable of mediating RNA interference against MMP13 gene expression and are useful for treating diseases and conditions that respond to modulation of MMP13 gene expression in a subject such as inflammatory diseases, disorders or conditions, including rheumatoid arthritis and osteoarthritis (paragraph 0003,0135-0137).
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable due to the claims encompassing treating an inflammatory disease which is a genus of arthritis in a subject by a genus of routes of administration and administering a conjugate comprising a genus of siRNAs capable of inhibiting expression of a large genus of proteins associated with the inflammatory disease. It would be unpredictable, given the millions of encompassed siRNA sequences capable of inhibiting expression of a protein associated with the inflammatory disease which is arthritis, and wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein, that any siRNA sequence would be capable of inhibiting expression of the protein associated with the inflammatory disease which is arthritis and result in the therapeutic effect.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
The specification does not enable any person skilled in the art to which it pertains to make and/or use the invention commensurate in scope with the claims. The instant specification only discloses 4 sequences for the siRNA, SEQ ID NO: 1,2,3,4 or a combination thereof (paragraph 0062). Page 61 of the instant specification shows that SEQ ID NO: 1 is the antisense sequence and SEQ ID NO: 2 is the sense sequence for the siRNA targeting mouse MMP13, and SEQ ID NO: 3 is the antisense sequence and SEQ ID NO: 4 is the sense sequence for the siRNA targeting Guinea Pig MMP13 and shows the chemical modifications of these sequences:
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Example 9 discloses Mouse and Guinea Pig MMP13 siRNA sequence screening including screening seven candidate siRNA sequences targeting different sites of the murine MMP13 gene and 4 candidate siRNA sequences targeting different sites of the guinea pig MMP13 gene, and that lead sequences were made into a 19-mer and formulated with stabilization chemistry i.e., “zipper” (paragraph 00143). The specific sequences screened are not disclosed and this example does not disclose that the lead sequences are SEQ ID NOs: 1-4. Example 9 discloses an in vivo therapeutic study of siMMP13<(EG18L)2 in a post-traumatic osteoarthritis (PTOA) mechanical loading mouse model (paragraph 00157), and in a Guinea pig anterior cruciate ligament model by intravenous administration (paragraph 00162). Results of the experiments are found on pages 56-57, and that the example conjugate, si<(EG18L)2 and the modified nucleotides aided properties of the siRNA including stability in synovial fluid and in-vitro carrier-mediated silencing (Fig. 1A,1B,1C,1D) and knockdown of murine MMP13 (Fig 1F) and binding to albumin in OA and RA human synovial fluid (Fig 1E) and that regular siRNA without lipophilic albumin-binding moieties did not have any appreciable MMP13 knockdown (Fig. 1F) or binding of albumin in human synovial fluid (Fig. 1E) (paragraph 00170). The conjugate was assessed in vivo in different inflammatory disease models and demonstrated preferential accumulation, retention and silencing of a target gene in an injured joint model of PTOA as shown in Fig. 2A-2I, 3A-3G, 4A-4G and 5A-5H. The conjugate also accumulated and had activity in all joints in a mouse model of rheumatoid arthritis (Fig. 6A-6G, 7A-7D, 8A-8G, 9A-9E) and that in both models intravenous delivery of the siRNA conjugate yielded accumulation in the affected joint, and the conjugate showed effective silencing in a guinea pig anterior cruciate ligament transection model (Fig. 10A-10F) (paragraph 00171). When designed against matrix metalloproteinase 13 (MMP13), the siRNA conjugate robustly silenced MMP13 expression in the joints. In both the PTOA and RA models, silencing of MMP 13 by systemic, intra-venous, treatment provided significant therapeutic benefits in terms of reducing joint inflammation, reducing cartilage loss, reducing synovial hyperplasia, maintaining bone homeostasis and reducing joint pressure sensitivity (pain). In-vivo subcutaneous studies (FIG. 11A - FIG. 11 C) show useful delivery and activity of siMMP13<(EG18L)2 at high doses and/or with the use of excipients. In-vivo local, intra-articular studies also show useful delivery, retention, and activity of siMMP 13<(EG18L)2 (FIG. 12A - FIG. 12F).
Therefore, the specification discloses methods of treating osteoarthritis, rheumatoid arthritis, post-traumatic osteoarthritis in a subject comprising administering by local, intra-articular, and intravenous administration, the conjugate of the siRNA of SEQ ID NOs: 1,2,3,4 (having the specific chemical modifications disclosed by these sequences described above) or combination thereof which targets mouse or guinea pig MMP13 conjugated to (EG18L)2 results in treatment of osteoarthritis, rheumatoid arthritis.
The Quantity of Experimentation Necessary
Regarding claims 1-4,6-20,22-33 and 35-39, in light of the unpredictability surrounding the breadth of the claimed method, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Millions of possible siRNA sequences that correspond to different target proteins associated with inflammatory diseases which are a genus of arthritis diseases and which hybridize to a genus of oligonucleotides encoding extracellular matrix degrading proteins and which are conjugated to different lipophilic ligands and linkers comprising branching molecules and hydrophilic spacers would need to be tested to determine if the recited method is capable of resulting in treatment of a genus of arthritic inflammatory diseases, and would be considered undue. As stated above, the specification only shows 4 siRNA sequences targeting MMP13 in osteoarthritis, rheumatoid arthritis or post-traumatic osteoarthritis model and the therapeutic effect thereof, as well as the specific lipophilic ligand and linker being (EG18L)2. Therefore, given the lack of guidance present in the specification for the recited method of treating, further experimentation would be required and would be considered undue.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 1-4,6-20,22-33 and 35-39, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 1-4,6-20,22-33 and 35-39 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Response to Arguments
Applicant's arguments and amendments, filed 07/20/2026 have been fully considered but they are not persuasive.
Applicant argues the Office’s analysis of enablement does not address the modified scope of the amended claims which are now directed to treating arthritis which should largely or completely address the Office’s concerns regarding the breadth of scope and nature of the invention. Regarding the scope of the enabled sequences, the Office’s analysis does not reflect advances in the state of the art for siRNA design since 2005 which have provided further rules for selection of proper sites for siRNA targeting, and again points to the Hofacker et al. reference provided in the written description arguments. Applicant argues that the claims specify proteins known in the art and that have known sequences, and that identification of relevant siRNA sequences of the claimed conjugates would be routine experimentation.
This is not found persuasive. While amending claim 1 to limit the inflammatory diseases to arthritis did help narrow the scope, the amendment does not overcome the rejection, and the arguments regarding siRNA design are not persuasive. MPEP 2164.03 states “in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims”. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because in art areas having a high degree of uncertainty (i.e. the unpredictable arts) it is not reasonably predictable from the disclosure of one species, what other species will work.
See also MPEP 2164.01, Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.
In the instant case, as the claims are directed to treatment methods, therefore physiological activity of compounds, and the claims are directed to a method of using a genus of siRNAs, and it is not predictable from the disclosure of 1 siRNAs provided by the instant application what other species of siRNAs directed to other extracellular matrix degrading proteins or even other siRNA sequences directed to other regions of MMP13 or even MMP13 from other species other than guinea pig and mouse, will work. For these reasons, the claims are not enabled for their full scope and the rejection is maintained.
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 1-4,6-20,22,23,25-33 and 35-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 and 23-40 of copending Application No. 18/737,720 (‘720) in view of McSwiggen et al. (US 20090099121, Published 16 April 2009).
Claims 1-40 of ‘720 recite a method of treating a central nervous system disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, optionally in combination with a pharmaceutically acceptable excipient, wherein the conjugate comprises a siRNA capable of inhibiting expression of a protein associated with the CNS disease; a lipophilic ligand capable of binding albumin; and a linker attaching the siRNA to the lipophilic ligand, the linker comprising a branching molecule attached to the siRNA, and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand. Claim 32 of ‘720 recites the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage.
Instant claims 1-4,6-20,22,23,25-33 and 35-39 recite a method of treating an inflammatory disease, wherein the inflammatory disease is arthritis, in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, optionally in combination with a pharmaceutically acceptable excipient, wherein the conjugate comprises a siRNA capable of inhibiting expression of a protein associated with the inflammatory disease, wherein the siRNA is capable of specifically hybridizing to an oligonucleotide encoding an extracellular matrix degrading protein, and recites the same limitation of the lipophilic ligand and linker as claim 1 of ‘720. Instant claim 1 also recites “wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage” as in claim 32 of ‘720.
‘720 does not recite a method of treating an inflammatory disease which is arthritis, or the same routes of administration as in instant claim 2, or that the siRNA hybridizes to an oligonucleotide encoding MMP13.
Before the effective filing date, McSwiggen et al. teach compounds, compositions, and methods for treatment of diseases and conditions that respond to modulation of matrix metalloproteinase 13 (MMP13) gene expression and/or activity, including short interfering nucleic acid (siNA) and short interfering RNA (siRNA) molecules capable of mediating RNA interference against MMP13 gene expression and are useful for treating diseases and conditions that respond to modulation of MMP13 gene expression in a subject such as inflammatory diseases, disorders or conditions, including rheumatoid arthritis and osteoarthritis (paragraph 0003,0135-0137). McSwiggen et al. teach a composition comprising an siRNA molecule of the invention in a pharmaceutically acceptable carrier or diluent, and a method of treating comprising administering to the subject a composition of the invention (paragraph 0150). Regarding the meaning of “siNA” used in McSwiggen et al., paragraph 0199 of McSwiggen et al. teach “As used herein, the term siNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA)…” (paragraph 0199).
McSwiggen et al. teach the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker.
Regarding the effective amount, the instant specification teaches a suitable dose will often be in the range of 0.01-1000 mg/kg, such as about 0.1 to about 100 mg/kg (paragraph 0091). McSwiggen et al. teach a pharmaceutically effective dose is that dose required to prevent, inhibit, the occurrence or treat of a disease state, and generally an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered (paragraph 0341).
McSwiggen et al. teach the nucleic acid molecules of the invention are administered via direct injection to the affected site (e.g. affected joint or associated synovial fluid in cases of treating rheumatoid arthritis or osteoarthritis) (paragraph 0327).
McSwiggen et al. teach a pharmaceutically effective dose is that dose required to prevent, inhibit, the occurrence or treat of a disease state, and generally an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered (paragraph 0341).
McSwiggen et al. teach MMPs act as regulatory molecules, both by functioning in enzyme cascades and by processing matrix proteins to generate fragments with enhanced or reduced biological effects and as a family the MMPs are capable of breaking down numerous extracellular matrix components (paragraphs 0365 and 0367), and the MMP family includes MMP13 (paragraph 0366).
It would have been obvious to one of ordinary skill in the art to use the siRNA conjugate comprising the lipophilic ligand and linker of ‘720 in a method of treating an inflammatory disease which is arthritis, in a subject in need thereof, and wherein the siRNA is capable of inhibiting expression of MMP13 based on the teachings of McSwiggen et al. There would be a reasonable expectation of success because McSwiggen et al. suggests the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker, and would amount to simple substitution of one known element for another to obtain predictable results. One of ordinary skill in the art would have been motivated to use such an siRNA conjugate comprising the structure of the lipophilic ligand and linker of ‘720 and apply to an siRNA that targets other proteins to treat other diseases, such as taught by McSwiggen et al. which teach compounds, compositions, and methods for treatment of diseases and conditions that respond to modulation of matrix metalloproteinase 13 (MMP13) gene expression and/or activity, including short interfering nucleic acid (siNA) and short interfering RNA (siRNA) molecules capable of mediating RNA interference against MMP13 gene expression and are useful for treating diseases and conditions that respond to modulation of MMP13 gene expression in a subject such as inflammatory diseases, disorders or conditions, including rheumatoid arthritis and osteoarthritis (paragraph 0003,0135-0137). McSwiggen et al. teach a composition comprising an siRNA molecule of the invention in a pharmaceutically acceptable carrier or diluent, and a method of treating comprising administering to the subject a composition of the invention (paragraph 0150), and that the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker.
This is a provisional nonstatutory double patenting rejection.
Claim 24 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 22 of copending Application No. 18/737,720 (‘720) in view of McSwiggen et al. (US 20090099121, Published 16 April 2009) as applied to claims 1-4,6-20,22,23,25-33 and 35-39 above and further in view of Nannuru et al. (WO 2011123394, Published 6 Oct 2011), Hassler et al. (Nucleic Acids Research, 2018 Vol. 46, No. 5, 2185-2196), and Gangopadhyay et al. (RNA Biology, 2022, Vol. 19, No. 1, 452-467).
Claim 22 of ‘720 recites the siRNA comprises a nucleotide sequence of SEQ ID NO: 1-17 or a combination thereof.
‘720 does not recite the siRNA comprising the nucleotide sequence of instant SEQ ID NO: 1.
Before the effective filing date, Nannuru et al. taught methods, compounds, compositions for inhibiting expression of MMP-13 mRNA and protein in an animal (Field of invention, page 1). Nannuru et al. taught methods of administering to an animal a therapeutically effective amount of a composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and comprising a nucleobase sequence comprising at least 12 contiguous nucleobases of the sequences recited in SEQ ID NOs: 8-85, and a pharmaceutically acceptable carrier (page 19). Nannuru et al. taught the antisense compounds targeted to MMP-13 have chemically modified subunits arranged in patterns, or motifs to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid or resistance to degradation by in vivo nucleases (page 24). Nannuru et al. taught an antisense oligonucleotide sequence targeting MMP-13 of SEQ ID NO: 16 with 72% inhibition of MMP-13, and which had 5-10-5 MOE wings (Table 4, pages 56-57). See alignment below wherein Qy is instant SEQ ID NO: 1 and Db is SEQ ID NO: 16 of Nannuru et al.:
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Nannuru et al. does not teach the specific chemical modification pattern required by instant SEQ ID NO: 1 shown on page 61 of the instant specification and the Sequence Listing.
Hassler et al. (Nucleic Acids Research, 2018, Vol. 46, No. 5, 2185-2196) teach that siRNA based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues, and that most clinically-advanced non-formulated compounds using conjugation as a delivery strategy are fully chemically modified (Abstract). Hassler et al. teach fully modified siRNAs are retained at 100x greater levels in various tissues, independent of the nature of the conjugate or the siRNA sequence and support productive miRNA silencing (Abstract, Introduction, page 2185). Hassler et al. teach GalNAc conjugated siRNAs that are fully modified with alternating 2’-fluoro, 2’-O-methyl pattern, and that recent fine-tuning of the chemical stabilization includes increasing the 2’-O-methyl content, incorporation of additional phosphorothioates, and 5- phosphate stabilization have been shown to further enhance long-term efficacy of conjugated siRNAs (Intro, page 2185).
Hassler et al. teach a fully chemically modified siRNA pattern shown in Figure 1A below which shows a 5’-phosphate at position 1, alternating 2’-O-methyl starting at position 1 and 2’-fluoro RNAs starting at position 2, and phosphorothioate linkages between positions 1 and 2 and 2 and 3 on the 5’ end, and between the last 7 nucleotides on the 3’ end.
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For comparison, the chemical modification pattern for instant SEQ ID NO: 1 which is found on page 61 of the instant specification (and the Sequence Listing) is shown below to aid in comparing the modification pattern.
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Hassler et al. teach testing the fully modified siRNA conjugated to cholesterol in vivo, and that though several configurations were functional, an alternating 2’-O-methyl, 2’–fluoro pattern, with a chemically monophosphorylated, 2’ -O-methyl-modified uridine (U) at position 1, and a 2’-fluoro modified nucleotide at position 14 of the guide strand performed the best (Figure 1A) and that an alternating pattern with a 2’ –fluoro in position 1 of the guide strand reduced silencing activity (data not shown), likely due to placement of 2’-O-methyl groups in positions 2 and 14, which negatively affects potency in the context of heavily modified duplexes. The guide strand was also 5’ -chemically phosphorylated, as terminal 2’-O-methylated U is not a good a substrate for intracellular kinases as natural RNA, and two phosphorothioate linkages to both 5’ and 3’ ends of the passenger and guide strands were added to provide additional resistance to exonucleases (page 2189, left column). Hassler et al. teach the fully modified hsiRNA loaded almost three times more RISC complex compared to the naked siRNA (Figure 1D), which is likely a result of the enhanced stability (page 2189, right column). Hassler et al. also teach that full chemical stabilization significantly enhances conjugate-mediated tissue accumulation independent of the conjugate nature, route of administration and is heavily reliant on the full chemical modification of the siRNA, and also that full chemical stabilization enables productive silencing (Page 2192).
Hassler et al. do not teach that there are only 2 phosphorothioate internucleotide linkages at the 3’ end of the antisense sequence as required by instant SEQ ID NO: 1.
Gangopadhyay et al. (RNA Biology, 2022, Vol. 19, No.1, 452-467) also teach various modifications and modification patterns of siRNA drugs that have been approved by the US FDA (Abstract). Gangopadhyay et al. teach the chemical modification pattern of 3 siRNA FDA approved drugs which are siRNA GalNaC conjugates, shown in Figure 2, which have 2’-O-methyl and 2’-fluoro modifications, as well as 2 phosphorothioate linkages at the last two positions at both the 5’ and 3’ end of the guide strand (antisense strand) (Fig 2 shown below). Gangopadhyay et al. teach replacing phosphodiester linkages with phosphorothioate linkages are explored to design and develop new oligonucleotides with improved RNAi activity, and that phosphorothioate modifications protect siRNA from 3’-exonucleases in vitro and in vivo, placement in the central position in the guide strand inhibits RNAi activity and PS modification increases cellular uptake of siRNAs (pages 461-462).
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Therefore, it would have been obvious to swap the siRNA sequences of ‘720 with an siRNA comprising SEQ ID: 16 as the antisense sequence as taught by Nannuru et al. which targets MMP-13 and use in the treatment method of McSwiggen et al., and to provide SEQ ID NO: 16 of Nannuru et al. with the modification pattern required by instant SEQ ID NO: 1, based on the teachings of Hassler et al. and Gangopadhyay et al. with a reasonable expectation of success. There would be a reasonable expectation of success because McSwiggen et al. suggests the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker, and because Nannuru et al. pertains to antisense sequence targeting the same gene, MMP13 and suggests chemically modified subunits arranged in patterns, or motifs to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid or resistance to degradation by in vivo nucleases, and Hassler et al. and Gangopadhyay et al. pertain to siRNA conjugates, chemical modifications, patterns and the benefits thereof.
One of ordinary skill in the art would have been motivated to use the antisense sequence which targets MMP13 comprising SEQ ID NO: 16 of Nannuru et al. as the antisense sequence of the siRNA used in the treatment method of McSwiggen et al. because Nannuru et al. taught methods of administering to an animal a therapeutically effective amount of a composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and comprising a nucleobase sequence comprising at least 12 contiguous nucleobases of the sequences recited in SEQ ID NOs: 8-85, and a pharmaceutically acceptable carrier (page 19) and that the antisense compounds targeted to MMP-13 have chemically modified subunits arranged in patterns, or motifs to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid or resistance to degradation by in vivo nucleases (page 24) and the antisense oligonucleotide sequence targeting MMP-13 of SEQ ID NO: 16 provided 72% inhibition of MMP-13, and would have amounted to selecting any of the taught MMP-13 sequences that provide MMP-13 inhibition from a list. One of ordinary skill in the art would have been motivated to provide the antisense sequence of SEQ ID NO: 16 of Nannuru et al. with a 5’-phosphate at position 1 on the 5’ end, phosphorothioate linkages at positions 1 and 2 and 2 and 3 of the 5’ end and positions 17 and 18 and 18 and 19 of the 3’ end, and alternating 2’-O-methyl and 2’-F modifications with the 2’-O-methyl starting at position 1 and the 2’-fluoro starting at position 2, because Hassler et al. taught a fully chemically modified siRNA pattern in Figure 1A with a 5’-phosphate at position 1, alternating 2’-O-methyl starting at position 1 and 2’-fluoro RNAs starting at position 2, and phosphorothioate linkages between positions 1 and 2 and 2 and 3 on the 5’ end, and between the last 7 nucleotides on the 3’ end performed the best (Figure 1A), that two phosphorothioate linkages to both 5’ and 3’ ends of the passenger and guide strands were added to provide additional resistance to exonucleases (page 2189, left column), that the fully modified hsiRNA loaded almost three times more RISC complex compared to the naked siRNA (Figure 1D), which is likely a result of the enhanced stability (page 2189, right column), that full chemical stabilization significantly enhances conjugate-mediated tissue accumulation independent of the conjugate nature, route of administration and is heavily reliant on the full chemical modification of the siRNA, and also that full chemical stabilization enables productive silencing (Page 2192). Additionally, Gangopadhyay et al. teach the chemical modification pattern of 3 siRNA FDA approved drugs which are siRNA GalNaC conjugates, shown in Figure 2, which have 2’-O-methyl and 2’-fluoro modifications, as well as 2 phosphorothioate linkages at the last two positions at both the 5’ and 3’ end of the guide strand (antisense strand), and that replacing phosphodiester linkages with phosphorothioate linkages are explored to design and develop new oligonucleotides with improved RNAi activity, and that phosphorothioate modifications protect siRNA from 3’-exonucleases in vitro and in vivo and increases cellular uptake of siRNAs (pages 461-462).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Regarding the above nonstatutory double patenting rejections, no arguments or response was provided by Applicant regarding these rejections. Therefore, the rejections stand.
Conclusion
Claims 1-4,6-20,22-33 and 35-39 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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