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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1,2,4-7,9 and 27-29) in the reply filed on 08/14/2025 is acknowledged.
Claims 10-16,18,19 and 21-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/14/2025.
Claims 1,2,4-7,9 and 27-29 are under examination.
Priority
This application is a CON of PCT/EP2020/086405 filed 12/16/2020 and claims foreign priority to EP19217771.5 filed 12/19/2019.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1,2,4-7,9 and 27-29 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.
The broadest reasonable interpretation of the claimed method is a SEPT9 inhibitor to treat or prevent an HBV infection in any subject. Such SEPT9 inhibitors could be small molecules, nucleic acid inhibitors, polypeptides, etc. In addition, claim 28 encompasses preventing or treating any disease in a subject with the recited nucleic acid molecule. The instant specification discloses that the term “compound” means any molecule capable of inhibiting SEPT9 expression or activity (page 6, lines 23-24). The SEPT9 inhibitor embraces a nucleic acid molecule that directly or indirectly inhibits SEPT9 expression in a subject having a HBV infection. The SEPT 9 nucleic acid molecule comprises an antisense oligonucleotide or another oligomeric nucleic acid molecule, such as CRISPR RNA, siRNA, shRNA, an aptamer or a ribozyme (instant specification pg. 7 lines 2-4).
Table 3 on page 17 of the instant specification provides a list of SEPT9 target sequences, including SEQ ID NOs: 1-3, as well as in Table 5A on page 66 with SEQ ID NOs: 4-7 being the target sequences, and discloses two antisense oligonucleotide sequences in Table 6, page 68, of SEQ ID NOs: 17 and 18. The specific antisense oligonucleotide sequences of SEQ ID NOs: 17 and 18 does not provide written support for the genus of SEPT9 inhibitors including types of molecules such as CRISPR RNA, aptamers and ribozymes, organic compounds and polypeptides. Antisense oligonucleotides, siRNA and shRNA have a different structure and/or mechanism of action compared to these other types of nucleic acid molecules as well as polypeptides and organic compounds. There is no essential structure of record required for SEPT9 inhibitors to treat or prevent HBV in a subject or to treat or prevent any disease in a subject as in claim 28, that would support written description for the genus of SEPT9 inhibitors. The skilled artisan cannot envision CRISPR RNA, aptamers and ribozymes having the desired biological activity (treat or prevent HBV infection or any disease in a subject by reducing SEPT9 expression) based on the nucleic acid inhibitors described in the specification. Other than generically contemplating these molecules, the specification does not provide adequate written description of the CRISPR RNA, aptamer, ribozyme itself. See MPEP 2163, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). While it is acknowledged that it is routine and conventional to prepare these molecules, in view of MPEP 2163, adequate written description of SEPT9 inhibitors requires more than just generically contemplating the species of inhibitors. In view of the lack of description for these species, the skilled artisan would have to use an assay to make these molecules and then empirically determine if they have the desired biological activity.
In addition, the prior art and the as-filed specification do not provide written description for any molecule that indirectly reduces SEPT9 expression in a cell infected with HBV.
The written description requirement for the claimed genus of SEPT9 inhibitors is not satisfied through sufficient description of a representative number of species. There is substantial variation within the genus of SEPT9 inhibitors, and the applicant does not describe a sufficient variety of species to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also 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.)
In view of the foregoing, it is clear that the instant specification fails to convey that the inventors had possession of the genus of SEPT9 inhibitors with the recited functions in claims 1,2,4-7,9 and 27-29 as of the effective filing date sought in the instant case.
Claim Rejections-Scope of Enablement
Claims 1,2,4-7,9 and 27-29 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 an in vitro method of inhibiting SEPT9 expression in a target cell expressing SEPT9 by administering a nucleic acid molecule as recited in instant claim 10 and being enabling for a method of treating HBV infection in a subject comprising administering a nucleic acid molecule as recited in instant claims 4-7, does not reasonably provide enablement for a method of preventing HBV infection or preventing any disease comprising administering a genus of SEPT9 inhibitors, or treating HPV infection or treating any disease comprising administering a genus of SEPT9 inhibitors. 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 1,2,4-7,9,28 and 29 encompass both treatment of an existing disease or prevention of a disease, i.e. prophylaxis. Prophylactic can be understood as preventing an HBV infection from turning into a chronic HBV infection or the prevention of severe liver diseases such as liver cirrhosis and hepatocellular carcinoma caused by a chronic HBV infection (pg. 4, lines 27-32). Claim 28 also encompasses treating or preventing any disease in a subject and is not limited to HBV infection.
Regarding the subject, this encompasses all possible mammalian subjects preferably, humans and mammals.
Regarding the administering step, this encompasses all ways of administering which includes but is not necessarily limited to: All routes of administration including topical, injection, inhalation, and others.
Regarding the SEPT9 inhibitor, this encompasses all possible agents that are capable of decreasing levels of SEPT9 mRNA including all possible proteins or RNA/DNA that encodes them that are present at any point in a biological pathway of SEPT9 mRNA or protein that would affect the pathway and result in an decrease of SEPT9 mRNA or protein including SEPT9 that directly or indirectly inhibits SEPT9 expression. This includes small molecules, nucleic acid inhibitors, polypeptides, and the nucleic acid molecule inhibitor encompasses an antisense oligonucleotide or another oligomeric nucleic acid molecule, such as CRISPR RNA, siRNA, shRNA, an aptamer or a ribozyme (instant specification pg. 7 lines 2-4).
Thus, the breath of claims is vast.
The State of the Prior Art and The Level of Predictability in the Art
The state of the art does not teach treating or preventing hepatitis B virus infection in a subject, or treating or preventing any disease in a subject (claim 28) by administering a genus of SEPT9 inhibitors.
As stated above, while Applicant’s claim specifically encompasses in vivo embodiments “in a subject,” Applicant only provides working examples in vitro.
However, WO 2017216390 (‘390), Published 21 Dec 2017 teaches treating HBV infection by administering nucleic acid molecules that inhibit expression and/or activity of PAPD7, including single stranded antisense, siRNA and shRNA molecules (page 5, lines 24-25), but does not teach administering SEPT9 inhibitors.
Montagna et al. (WO 2004074441, Published 2 Sept 2004), teach a method of inhibiting a protein encoded by a Septin9 gene and that siRNAs were designed and transiently transfected into cells with and without Sept9 overexpression (Example 3, paragraphs 0087-0088). Montagna et al. teach the Sept9 siRNA sense strand is SEQ ID NO: 8 and the antisense strand is SEQ ID NO: 9, and the siRNA duplex mixture was added to cultured cells (paragraph 0088), and a mRNA expression decrease of 28.8-58% was observed in the three cell lines with Sept9 overexpression (paragraph 0089). Montagna et al. teach this example demonstrates that the protein encoded by the Septin9 gene can be inhibited by the siRNAs described herein (paragraph 0090).
Therefore it was known in the art that HBV could be treated by administering nucleic acid based inhibitors (antisense, siRNA, shRNA), and that the state of the art teaches specific siRNA sequences targeting SEPT9 that result in decreased expression.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
Regarding claims 1,2,4-7,9 and 27-29, 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 specification does not show how the recited methods of preventing HBV infection or preventing any disease in a subject with a genus of SEPT9 inhibitors would be carried out, not does the specification describe how the recited method of treating HBV infection or treating any disease in a subject would be carried out with a genus of SEPT9 inhibitors.
It is noted that the claims do not recite a specific nucleotide range by SEQ ID NO, but rather refer to the broad genus of any sequence within the genus of sequences of mammalian SEPT9 genes including all variants. The instant claims embrace contacting any biological system via any means of delivery with any antisense oligomer with the proviso that 12 contiguous nucleotides are at least 95% (claim 4) identical to a mammalian SEPT9 target sequence. It is highly unpredictable that sequences without a particular locus to target would in fact be specific for SEPT9 (or any given target).
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 delivering an antisense oligomer with minimal specificity to a target sequence and the resultant in vivo effects.
MPEP 2164.01 Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a) A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Method of treating or preventing (in vivo); i.e., in vitro-in vivo correlation
As discussed for the written description section above, there is no disclosure on how treatment or prevention is achieved. Only in vitro treatment of a cell line is described. The practice of a method without the need for substantial undue experimentation and additional inventive contribution requires the disclosure of an effective route, duration and quantity of administration of that inhibitor to a subject and this information is not provided by the instant specification. The background text on page 1 of the instant specification clearly fails to supply the guidance that would be needed by a routine practitioner. In fact, this paragraph says, see quotation: The presence of a few copies of cccDNA might be sufficient to reinitiate a full-blown HBV infection.
The instant disclosure shows results of decrease in cccDNA. However, this decrease is not 100%; i.e., a few copies of cccDNA remain. Therefore, one would not be able to reconcile the decrease seen by following instant method and achieving any treatment or prevention in a subject.
The Quantity of Experimentation Necessary
The instant specification has also failed to disclose how the parameter measured in vitro may be translated to determine prevention has been achieved in vivo, how a similar method was practiced in the art with a different agent or to provide even a single working example, prophetic or actual, of the claimed method. In the absence of this guidance a practitioner would have to resort to a substantial amount of undue experimentation involving the variation in the amount and duration of administration of a SEPT9 inhibitor of the instant invention and in determining a suitable route of administration. 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.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 1,2,4-7,9 and 27-29, 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 1,2,4-7,9 and 27-29 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.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim 27 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Montagna et al. (WO 2004074441, Published 2 Sept 2004).
Montagna et al. teach the Septin9 (Sept9) gene, also known as SL3-3 integration site-1 (Sint1) gene was first described as a gene in mouse that encodes a protein (Septin9) of 334 amino acids, and that the coding sequences of the Septin9 gene are publicly available at the NCBI website as GenBank Accession No. NM_017380 and NP_059076 and are disclosed herein as SEQ ID NO: 3 and SEQ ID NO: 5 respectively (paragraph 0014).
Montagna et al. teach a method of inhibiting a protein encoded by a Septin9 gene and that siRNAs were designed, transfections of reporter plasmid and siRNA were performed with oligofectamine, and 3 ml oligofectamine diluted in Opti-MEM were applied to the siRNA duplex mixture (60 pmole in 3 ml annealing buffer), incubated at room temperature, and the siRNA duplex oligofectamine mixture was added to cultured cells (40-50% confluent, and transfection was carried out for 48 hours (Example 3, paragraphs 0087-0088). Montagna et al. teach the Sept9 siRNA sense strand is SEQ ID NO: 8 and the antisense strand is SEQ ID NO: 9, and a mRNA expression decrease of 28.8-58% was observed in the three cell lines with Sept9 overexpression (paragraph 0089). Montagna et al. teach this example demonstrates that the protein encoded by the Septin9 gene can be inhibited by the siRNAs described herein (paragraph 0090). Therefore, as Montagna et al. teach administering specific amounts of the siRNA to a cell in vitro, which results in a decrease of expression of SEPT9 in the cell, Montagna et al. teach administering effective amounts of the nucleic acid molecule.
Regarding the nucleic acid molecule used, the antisense strand of SEQ ID NO: 9 of Montagna et al. is 19 nucleotides long and is 100% complementary to the mouse Septin 9 coding sequence of GenBank Accession No. NM_017380 which is SEQ ID NO: 3 of Montagna et al. See alignment below, wherein Qy is SEQ ID NO: 9 of Montagna et al. (the Sept9 antisense sequence) and Db is the nucleotide sequence of GenBank Accession No. NM_017380 which is SEQ ID NO: 3 of Montagna et al.
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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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1,2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017216390 (‘390), Published 21 Dec 2017 in view of Xu et al. (Oncotarget, Vol.7, No. 43, Published 30 Sept 2016, pp. 70559-70574), both cited on an IDS.
Regarding claim 1, ‘390 teaches a method of treating an HBV infection, wherein the method comprises administering an effective amount of the inhibitor of the invention, in particular a nucleic acid molecule to a subject in need of such a treatment (page 29, lines 14-18), and that the inhibitor of the present invention is an RNAi molecule against PAPD5 or PAPD7 (page 14, 27-30). ‘390 teaches regarding the effective amount, also known as therapeutically effective dose, factors for consideration include the particular mammal being treated, clinical condition of the patient, site of delivery to the agent, method of administration, scheduling of administration, age and sex of the patient, and for example if the PAPD5 inhibitor or PAPD7 inhibitor is an antisense oligonucleotide, then the pharmaceutically effective amount administered is a dose of 0.1-15mg/kg (page 41, lines 15-27).
‘390 does not teach targeting SEPT9 with an inhibitor.
Xu et al. cures this deficiency. Xu et al. teaches Hepatitis B virus X protein (Hbx) participates in the occurrence and development processes of hepatocellular carcinoma as a multifunctional regulation factor, and use p21Hbx/+ mice to identify differentially expressed proteins, and that lipid metabolism and CDC42-induced cytoskeleton remodeling pathways were strongly activated by the Hbx transgene and provide evidence that HbX induces the dysregulation of cytoskeleton remodeling and lipid metabolism (Abstract). Xu et al. teach that activation of CDC42, CFL1, SEPT9, ADFP and PPAR result in the cytoskeletal remodeling and lipid metabolism caused by transfected HBx in hepatocarcinogenesis (page 70563, right column). Xu et al. teach SEPT9 polymerizes into hetero-oligomeric protein complexes resulting in formation of filaments which could associate with cellular membranes, actin filaments and microtubules, and found that SEPT9 increased about 3-fold in 24M p21Hbx/+ than in 12M p21Hbx/+ and the WT littermate mice (page 70564, left column). Xu et al. teach the accumulation of cytoskeleton remodeling-related proteins in 24M p21Hbx/+ samples including SEPT9. Xu et al. teach SEPT9 belongs to the family of GRP-binding proteins which enhances the formation of filamentous structures and cytoskeleton by serving as a scaffold protein to recruit other proteins to specific subcellular structures, and that the results support the hypothesis that dysregulation of cytoskeletal remodeling generates the occurrence and development of HBx-induced HCC (page 70567, right column).
Regarding claim 2, ‘390 teaches HBV infection remains a major health problem worldwide which concerns an estimated 350 million chronic carriers who have a higher risk of liver cirrhosis and hepatocellular carcinoma (page 1, lines 32-34).
Regarding claim 5, ‘390 teaches nucleic acid molecules that inhibit expression and/or activity of PAPD7, including single stranded antisense, siRNA and shRNA molecules (page 5, lines 24-25). ‘390 teaches “HBV infection” includes acute and chronic hepatitis B infection (page 66, lines 28-29).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the target molecule being inhibited to SEPT9 in the method of treating an HBV infection of ‘390 based on the teachings of Xu et al. regarding SEPT9. One of ordinary skill in the art would have been motivated by Xu et al. to target SEPT9 in order to treat an HBV infection, because Xu et al. shows that SEPT9 levels are increased during HBV infection due to the dysregulation of cytoskeleton remodeling, and one of ordinary skill in the art would consider SEPT9 as a promising target in the treatment of HBV infections. Regarding the therapeutically effective amount, an ordinary artisan would be able to administer a therapeutically or prophylactically effective amount of the specific inhibitor based the teachings of ‘390 which teach the effective amount varies based on the mammal being treated, clinical condition, site of delivery and method of administration, scheduling of administration, age and sex of the patient and for example teaches a pharmaceutically effective amount administered is a dose of 0.1-15mg/kg of an antisense oligonucleotide inhibitor (page 41, lines 26-27). The instant specification discloses that the nucleic acid molecule of the invention is administered at a dosage of 0.1-15mg/kg (Page 54, lines 20-22). Therefore, ‘390 and the instant specification teach the same dosage, or “therapeutically effective amount” of nucleic acid inhibitor administered to the subject to treat HBV.
Accordingly the limitations of claims 1,2 and 5 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 4,6,7,9 and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017216390 (‘390), and Xu et al. as applied to claims 1,2 and 5 above, and further in view of Montagna et al. (WO 2004074441, Published 2 Sept 2004) as evidenced by NCBI Reference Sequence: NM_017380.2 and NCBI Reference Sequence: XM_113892.2.
The teachings of ‘390 and Xu et al. as applicable to claims 1,2 and 5 are described above.
‘390 also teaches the nucleic acid inhibitor is an antisense oligonucleotide which comprises a contiguous nucleotide sequence of 10-30 nucleotides in length, and may be at least 95% complementary to the target nucleotide sequence (page 16, lines 17-18,28-30).
‘390 and Xu et al. do not teach a Sept9 nucleic acid molecule inhibitor comprising a contiguous nucleotide sequence of at least 12 nucleotides in length and which is at least 95% complementary to a mammalian SEPT9 target sequence, or wherein the mammalian SEPT9 target sequence is SEQ ID NO: 1, or wherein the contiguous nucleotide sequence is at least 98% complementary to the target sequence of SEQ ID NO: 1 and SEQ ID NO: 2.
Montagna et al. cures this deficiency. Montagna et al. teach the Septin9 (Sept9) gene, also known as SL3-3 integration site-1 (Sint1) gene was first described as a gene in mouse that encodes a protein (Septin9) of 334 amino acids, and that the coding sequences of the Septin9 gene are publicly available at the NCBI website as GenBank Accession No. NM_017380 and NP_059076 and are disclosed herein as SEQ ID NO: 3 and SEQ ID NO: 5 respectively (paragraph 0014). Montagna et al. teach the MSF gene, also known as AF17q25 is the human ortholog of mouse Septin9, and the coding sequence of the MSF gene and the amino acid sequence of the protein are publicly available at the NCBI website as GenBank Accession No. XM_113892 and XP_113892 and are disclosed as SEQ ID NO: 4 and 6 respectively (paragraph 0015).
Montagna et al. teach a method of inhibiting a protein encoded by a Septin9 gene and that siRNAs were designed and transiently transfected into cells with and without Sept9 overexpression (Example 3, paragraphs 0087-0088). Montagna et al. teach the Sept9 siRNA sense strand is SEQ ID NO: 8 and the antisense strand is SEQ ID NO: 9, and the siRNA duplex mixture was added to cultured cells (paragraph 0088), and a mRNA expression decrease of 28.8-58% was observed in the three cell lines with Sept9 overexpression (paragraph 0089). Montagna et al. teach this example demonstrates that the protein encoded by the Septin9 gene can be inhibited by the siRNAs described herein (paragraph 0090).
The antisense strand of SEQ ID NO: 9 of Montagna et al. is 19 nucleotides long and is 100% complementary to the mouse Septin 9 coding sequence of GenBank Accession No. NM_017380 which is SEQ ID NO: 3 of Montagna et al. See alignment below, wherein Qy is SEQ ID NO: 9 of Montagna et al. (the Sept9 antisense sequence) and Db is the nucleotide sequence of GenBank Accession No. NM_017380 which is SEQ ID NO: 3 of Montagna et al.
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Montagna et al. teach the GenBank Accession No. (XM_113892) of the human ortholog of mouse Sept9 was publicly available before the effective filing date, and alignment of the sequence of XM_113892 and instant SEQ ID NO: 1 shows a best local similarity of 99.2% between nucleotides 1903-3985 of XM_113892 to nucleotides 217943-92665 of instant SEQ ID NO: 1. Additionally, alignment of the sequence of XM_113892 and instant SEQ ID NO: 2 shows a best local similarity of 90.4% between nucleotides 1903-3985 of XM_113892 to nucleotides 211693-213793 of instant SEQ ID NO: 2.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the nucleic acid inhibitor used in the HBV treatment method of ‘390 in view of Xu et al. with respect to the nucleic acid which is at least 95% complementary to a mammalian SEPT9 target sequence based on the teachings of Montagna et al. with a reasonable expectation of success. There would be a reasonable expectation of success as the nucleic acid inhibitor which may be siRNA of ‘390 is 10-30 nucleotides in length, and may be at least 95% complementary to the target nucleotide sequence (page 16, lines 17-18,28-30) and is used to treat HBV, and the Sept9 siRNA of Montagna et al. is 19 nucleotides long and is 100% complementary to the mouse Septin 9 coding sequence of GenBank Accession No. NM_017380 (a mammalian Sept9 target sequence). As the mouse and human Sept9 coding sequences were taught as publicly available before the effective filing date of the claimed invention by Montagna et al., it would be within the skill level of an ordinary artisan to design siRNAs targeting mouse or human Sept9 of the disclosed length that are at least 95% complementary to the mouse or human Sept9 target sequences.
Additionally, as Montagna et al. teach the GenBank Accession No. (XM_113892) of the human ortholog of mouse Sept9 was publicly available before the effective filing date, and alignment of the sequence of XM_113892 and instant SEQ ID NO: 1 shows a best local similarity of 99.2% between nucleotides 1903-3985 of XM_113892 to nucleotides 217943-92665 of instant SEQ ID NO: 1 and alignment of the sequence of XM_113892 and instant SEQ ID NO: 2 shows a best local similarity of 90.4% between nucleotides 1903-3985 of XM_113892 to nucleotides 211693-213793 of instant SEQ ID NO: 2, an ordinary artisan would be able to design siRNAs 12-60 nt in length with at least 12 contiguous nucleotides that are at least 95% complementary to instant SEQ ID NO: 1 or at least 12 contiguous nucleotides that are at least 98% complementary to instant SEQ ID NO: 1 and SEQ ID NO: 2 based on the similarity of instant SEQ ID NOs: 1 and 2 to the publicly available sequence of the human SEPT9 ortholog taught by Montagna et al. One of ordinary skill in the art would be motivated by the teachings of Montagna et al. that the Sept9 siRNA with the sense strand of SEQ ID NO: 8 and the antisense strand is SEQ ID NO: 9, and the siRNA duplex mixture resulted in mRNA expression decrease of 28.8-58% in the three cell lines with Sept9 overexpression (paragraph 0089) and demonstrates that the protein encoded by the Septin9 gene can be inhibited by the siRNAs described herein (paragraph 0090). An ordinary artisan would be motivated to apply the teachings to target cells expressing SEPT9 in vitro or in vivo, in order to inhibit HBV and treat an HBV infection.
Regarding the effective amount in claims 27-29, an ordinary artisan would be able to administer a therapeutically or prophylactically effective amount of the specific inhibitor based the teachings of ‘390 which teach the effective amount varies based on the mammal being treated, clinical condition, site of delivery and method of administration, scheduling of administration, age and sex of the patient and for example teaches a pharmaceutically effective amount administered is a dose of 0.1-15mg/kg of an antisense oligonucleotide inhibitor (page 41, lines 26-27). The instant specification discloses that the nucleic acid molecule of the invention is administered at a dosage of 0.1-15mg/kg (Page 54, lines 20-22). Therefore, ‘390 and the instant specification teach the same dosage, or “therapeutically effective amount” of nucleic acid inhibitor administered to the subject to treat HBV.
Accordingly, the limitations of claims 4,6,7 and 27-29 would have been prima facie obvious to one of ordinary skill in the art.
Regarding claim 9, while ‘390, Xu et al. and Montagna et al. are silent with respect to the wherein clause (functional limitation) of instant claim 9, ‘390 does teach the same amount of a nucleic acid inhibitor administered as the instant specification as cited above (dosage of 0.1-15mg/kg) that would result in the claimed function of reducing the amount of SEPT9 mRNA by at least 60%. Therefore, Xu et al. and Montagna et al. make obvious all of the claimed active method steps, so the functional effects of the claimed methods are considered to be embraced in the method steps made obvious by ‘390, Xu et al. and Montagna et al.
Accordingly, the limitations of claim 9 would have been prima facie obvious to one of ordinary skill in the art.
Conclusion
Claims 1,2,4-7,9 and 27-29 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636