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 .
Applicant’s response (amendments, arguments) filed with the RCE is acknowledged.
Claims 1, 8-10, 16-19, and 23, after amendments, remain pending and examined on the merits as drawn to e.g. peptide SEQ ID NO: 23 (labeled Hepalotide).
The examiner remains open to interview to advance prosecution on the merits.
Claimed Invention v. Prior Art of Record – Previously Noted
Applicant had concluded in their arguments filed 9/24/21 that they had ‘unexpectedly’ also found that the acyclic (aka the native linear version) of this known and native HBV fragment peptide SEQ ID NO 23 (which applicant calls Hepalotide):
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Previously upon review, applicant’s arguments appeared persuasive that the prior art of record only taught or suggested administration of a cyclic version of this peptide for the claimed NAFLD.
However, upon carrying out the updated interference search, which led to a closer review of applicant’s previous prior art of record. There it was uncovered in previously cited WO 2017102906 (see equivalent U.S. Patent Publication 20180354993, para [0264]), that such teaches the peptide SEQ ID NO: 23 (Hepalotide) in cyclic form and other equivalent derivatives in linear (acyclic) form, for treating NAFLD (‘993, para’s [0197], [0212], and [0250]), and that the cyclic form appears to work as well as the linear (acyclic) form:
[0264] B, The inhibitory activity of Myr-2-48 Cyc is comparable to other Myrcludex B derivatives, such as a linear Myrcludex B derivative with myristoyl group within the peptide sequence (2-Myr-48) and a linear preS-derives peptide 2-21 with a C-terminal myristoyl group (2-21-Myr).
Applicant’s Liu’s earlier work in WO 2015000371 (U.S. Patent Publication equivalent 20170112898) also teach the linear (acyclic) native peptide, but not the cyclic version and not for treating NAFLD. Thus, while '906 is ‘focused’ on the cyclic version (rather than the linear or acyclic version) of peptide SEQ ID NO: 23 (Hepalotide) for use in treating NAFLD, ‘906 is equally found to teach and/or suggest use of the instantly claimed linear or acyclic versions thereof for treating NAFLD (see ‘906, para [0264]).
Claim Rejections - 35 USC § 103 –Obviousness, Maintained
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 8-10, 16-19, and 23 remain rejected, after amendments, under 35 U.S.C. 103 as being unpatentable over Alexandrov (U.S. Patent Application No: 2018/0296634) in view of:
WO 2017/102906 A1 (RUPRECHT-KARLS-UNIVERSITAT HEIDELBERG), 22.June 2017 (22.06.2017) “WO ‘906”; equivalent U.S. Patent Publication 20180354993);
CN 103402545 A (RUPRECHT KARLS UNIVERSITAT HEIDELBERG), 20 November 2013 (20.11.2013) “CN ‘545”);
and further in view of Belanoff et al. (U.S. Patent Publication No. 20160106749).
As recited in the Advisory Action, but no further amendments and/or correspondence received thereto, the disposition is maintained that: based on the prior art of record or the prior art of record in view of Alexandrov, U.S. Patent Application No: 2018/0296634, which teaches/suggests: at least 13 of the claimed peptides (see RN #'s in search report within the file wrapper; Ref. 1 of 6) as well as teach/suggest that one of the proposed uses is for that of nonalcoholic steatohepatitis (see para's 14, 47, and Table 25) and that such may at a minimum decrease liver fibrosis (para 15, Table 15, claim 13).
WO ‘906 (abstract, tables, sequence list) discloses the use of a pharmaceutical composition comprising cyclic NTCP targeting peptides which are preS-derived peptides of the hepatitis B virus (HBV) in the treatment of a liver disease, such as non-alcoholic fatty liver disease (NAFLD), wherein the preS-derived peptide refers to a peptide with an amino acid sequence of the N-terminal extensions of the L-protein of HBV, i.e. preSl, preferably an amino acid sequence of hepatitis B viruses of genotypes A to H, but also refers to variants thereof, such as N-terminally and/or C-terminally truncated variants, and amino acid substitution variants. WO ‘906 discloses that the cyclic peptide contains amino acid residues 8 to 16 of the preS sequence and additionally contains amino acid residues 20 to 26 or 20 to 48 of the preS sequence; the sequences of SEQ ID NO: 21 and 24 in WO ‘906 are identical to sequences as shown in SEQ ID NO: 3, 23 and 31 of the present application; the cyclic peptide is hydrophobically modified, wherein the hydrophobic modification is an acylation of hydrophobic moieties, such as myristoyl, palmitoyl or stearoyl, or is an addition of hydrophobic moieties, selected from cholesterol, cholesterol derivatives, phospholipids, glycolipids, glycerol esters, steroids, ceramids, isoprene derivatives. WO ‘906 also teaches that non-alcoholic steatohepatitis (NASH) is the most extreme form of NAFLD. WO ‘906 teaches the route of administration is selected from oral, subcutaneous, intravenous, nasal, intramuscular, transdermal, inhalative, and by suppository.
See also in the equivalent U.S. Patent Publication 20180354993, para [0264]), that teaches the peptide SEQ ID NO: 23 (Hepalotide) in cyclic form and other equivalent derivatives in linear (acyclic) form, for treating NAFLD (‘993, para’s [0197], [0212], and [0250]), and that the cyclic form appears to work as well as the linear (acyclic) form:
[0264] B, The inhibitory activity of Myr-2-48 Cyc is comparable to other Myrcludex B derivatives, such as a linear Myrcludex B derivative with myristoyl group within the peptide sequence (2-Myr-48) and a linear preS-derives peptide 2-21 with a C-terminal myristoyl group (2-21-Myr).
CN ‘545 (abstract) discloses a pharmaceutical composition comprising hydrophobic modified peptides derived from preS-domains of HBV (though not expressly peptide SEQ ID NO: 23 per se), for use in the treatment of liver diseases such as non-alcoholic fatty liver disease (NASH). CN ‘545 discloses that the amino acid sequence of the preS peptide is based on the N-terminal extensions of the L-protein of HBV, i.e. preSl, preferably of hepatitis B viruses of genotypes A to H, but also refers to amino acid substitution or deletion variants or prolonged variants; the hydrophobic modification is selected from: acylation with myristoyl, palmitoyl or stearoyl; and the addition of hydrophobic moieties is selected from: cholesterol, cholesterol derivatives, phospholipids, glycolipids, glycerol esters, steroids, ceramids, isoprene derivatives, etc.; the C-terminal modification is a moiety that protects against degradation selected from: amides, D-amino acids, modified amino acids, cyclic amino acids, albumins, natural and synthetic polymers, etc.; and the route of administration is selected from subcutaneous, intravenous, oral, nasal, intramuscular, transdermal, inhalative, and by suppository.
Regarding claims 9 and 18-19, neither WO ‘906 or CN ‘545 discloses where a second agent is part of treatment. Notwithstanding that such would have been obvious for a person skilled in the art to administer two agents aimed at increasing effect, the examiner simply cites by example Belanoff, who teaches combination therapy for NAFLD, where the 2nd agent may be any number of those in instant claim 18 and 19 (e.g. orlistat).
Regarding claim 17, where the C-terminal modification is amidation or isopentanediolization, merely by example amidation of the C-terminus is standard art-recognized protecting group practice in the peptide arts and is prima facie obvious to apply (MPEP 2144.03 Official Notice taken). However, if applicant has some unique reason for the option isopentanediolization that would not have been led to by the art or showed some unexpected result, applicant may present evidence for such consideration.
Regarding new claim 23, such simply identifies a known species (m. acid).
Thus, the instantly claimed invention is deemed prima facie obvious based on the mnew prior art combination applied: based on the prior art of record or the prior art of record in view of Alexandrov, which teaches/suggests: at least 13 of the claimed peptides (see RN #'s in search report within the file wrapper; Ref. 1 of 6) as well as teach/suggest that one of the proposed uses is for that of nonalcoholic steatohepatitis (see para's 14, 47, and Table 25) and that such may at a minimum decrease liver fibrosis (para 15, Table 15, claim 13).
Response to Amendment/Arguments Filed by RCE
Applicant’s amendments and arguments have been fully considered but not yet found persuasive.
Amendments: The amendments have added to the preamble treating known symptoms of NAFLD/steatohepatitis, e.g. decreasing serum ALT and/or AST levels, as treatable by the linear peptide SEQ ID NO: 23 (containing the known K45Q substitution per the previously cited evidentiary referenced to Liu in 2005).
Arguments: Applicant does not dispute that the K45Q substitution was known in the art, based on the prior art of record and cited in applicant’s response (see e.g. Table in response). Applicant next argues that once of ordinary skill in the art would not have been motivated to make the K45Q substitution here (SEQ ID NO: 23) because of IC50 v. IC90 result variability tied to hepatitis B.
Response: This is not found persuasive as the results argued are not tied to or commensurate in scope with the instant claims and that to be treated. In other words that treated has not itself been shown to have yielded secondary considerations of unexpected results based on this K45Q substation – which was known in the art. Without such control data commensurate in scope with that claimed, the arguments are deemed to fall short, without further evidence.
For these reasons, the prima facie case of obviousness is maintained over the prior art of record and the state of the art as to the known K45Q substitution.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAURY AUDET whose telephone number is (571)272-0960. The examiner can normally be reached on M-Th. 7AM-5:30PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MAURY A AUDET/Primary Examiner, Art Unit 1654
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