DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1 and 52-55 are pending.
Claims 1 and 52-55 are under examination.
Withdrawn Claim Rejections - 35 USC § 112b
The rejection of claims 14 and 51 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the cancellation of these claims.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claims 8, 12, 14 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Levin et al. (WO-2010/041241-A2; see IDS filed 22nd, February, 2021; henceforth “Levin”) in view of Zhang et al. (CN 1903172 A; pages refer to attached translation; henceforth “Zhang”), Moloughney et al. (Recent Pat Biotechnol. 2012 Dec;6(3):200-11.; henceforth Moloughney), Klayko (2015, accessed at: https://brokensidewalk.com/2015/average-weight/), Doyle et al. ( 2016, accessed at https://web.archive.org/web/20160203033952/https://opentextbc.ca/clinicalskills/chapter/6-8-iv-push-medications-and-saline-lock-flush/ ; henceforth “Doyle), Wilson (WO 2017/120470 A1), Jain et al. (AAPS PharmSciTech. 2010 Jun;11(2):826-31.; henceforth “Jain”) and Baheti et al. (J. Excipients and Food Chem. 2010 May;1(1):41-54; henceforth “Baheti”) as set forth in the previous office action is withdrawn in view of the cancellation of these claims.
Claim Rejections - 35 USC § 103
Claims 1 and 52-55 are rejected under 35 U.S.C. 103 as being unpatentable over Levin et al. (WO-2010/041241-A2; see IDS filed 22nd, February, 2021; henceforth “Levin”) in view of Zhang et al. (CN 1903172 A; pages refer to attached translation; henceforth “Zhang”), Moloughney et al. (Recent Pat Biotechnol. 2012 Dec;6(3):200-11.; henceforth Moloughney), Klayko (2015, accessed at: https://brokensidewalk.com/2015/average-weight/), Doyle et al. ( 2016, accessed at https://web.archive.org/web/20160203033952/https://opentextbc.ca/clinicalskills/chapter/6-8-iv-push-medications-and-saline-lock-flush/ ; henceforth “Doyle), Wilson (WO 2017/120470 A1), Jain et al. (AAPS PharmSciTech. 2010 Jun;11(2):826-31.; henceforth “Jain”) and Baheti et al. (J. Excipients and Food Chem. 2010 May;1(1):41-54; henceforth “Baheti”).
Regarding claim 1, Levin discloses a pharmaceutical composition comprising:
a salt of a human HIV-1 integrase stimulatory (INS) peptide comprising the amino acid sequence of SEQ ID NO:1, (SEQ ID NO: 6 of Levin), and
a pharmaceutically acceptable carrier (pg. 3, 7, 9, 19, 31-33; claims 1, 3, 8, 18, 26).
However, regarding the poloxamer of claim 1, although Levin teaches the composition may include a poloxamer (pluronic; pg. 17-18), Levin is silent to the poloxamer of poloxamer 188, which is the structure of Formula I where a is 80 and b is 27.
Nevertheless, regarding claim 1, Zhang teaches a composition comprising a peptide and poloxamer 188 (F68; pg. 2). Zhang teaches including poloxamer 188 in the composition with the peptide helps the peptide better retain its biological activity, increases the stability, prolongs half-life in vivo, improves solubility and reduces immunogenicity, and also forms a micelle to increase the solubility of an insoluble drug (pg. 2 3rd para).
Additionally, regarding claim 1, Moloughney teaches the use of Poloxamer 188 in biomedical applications (P188; pg. 2-4). Moloughney teaches that Poloxamer 188 is well tolerated upon repeated exposure, has been demonstrated to be safe when given for up to 72 hours, had been approved by the FDA for more than 50 years, and has an ability to repair damaged cell membranes (pg. 3)
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the pharmaceutical composition of Levin, and combine the known prior art element of the Poloxamer 188 of Zhang to obtain the predictable result of a pharmaceutical composition. One of ordinary skill would have been motivated to do so as taught by Zhang to help the peptide better retain its biological activity, increase the stability, prolong half-life in vivo, improve solubility and reduce immunogenicity, and to form a micelle and increase the solubility of an insoluble drug (pg. 2). Furthermore, one would have been motivated to do so as taught by Moloughney, who review the use Poloxamer 188 in biomedical applications (P188; pg. 2-4), and teaches that Poloxamer 188 is well tolerated upon repeated exposure, has been demonstrated to be safe when given for up to 72 hours, had been approved by the FDA for more than 50 years, and it has an ability to repair damaged cell membranes (pg. 3). Regarding the reasonable expectation of success, Zhang evidences a composition for pharmaceutical use comprising a peptide and poloxamer 188 (F68; pg. 2).
However, regarding the concentration of the INS peptide of claim 1, the composition as suggested by Levin, Zhang and Moloughney are silent to an amount of the salt of the peptide of from 5 to 10 mg/ml.
Nevertheless, regarding claim 1, Levin teaches the composition can be given in the form of an injection and may be given intramuscularly (pg. 19-20). Levin teaches the amount of the active ingredient in should be in the range of 10 to 5000 µg/kg, and can be given to a human subject (21).
Additionally, regarding claim 1, Klayko teaches the average weight of an adult in the United States is 82 kg (about 180.9 lbs male and females averaged; pg. 1).
Lastly, regarding claim 1, Doyle teaches intramuscular injections of medications for clinical use in humans, with the maximum amount of volume injected in a single dose to deltoid muscle injection as 1 mL (pg. 1, 3).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the composition as suggested by Levin in view of Zhang and Moloughney, and combine the known prior art element of concentration of 0.8 mg/mL to 410 mg/mL of the peptide salt (corresponding to a 1 mL dose of 10 to 5000 µg/kg intramuscular injection for an average human adult at 82 kg) of Levin to obtain the predictable result of a concentration suitable for intramuscular injection. One of ordinary skill would have been motivated to do so as taught by Doyle because the 1 mL intramuscular injection would allow the composition to work well for a quick absorption rate and prolonged action (pg. 1). Regarding the reasonable expectation of success, Doyle evidences intramuscular injections and concentrations (pg. 1, 3).
Notably, regarding claim 1, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05. Therefore in the instant case, the suggested range of 0.8 mg/mL to 410 mg/mL overlaps with the instantly claimed range of 5 to 10 mg/mL and thereby makes it obvious.
However, regarding claim 1, although Levin teaches a salt of the peptide, which may be an inorganic salt (pg. 15), Levin does not teach the salt is hydrochloride salt.
Nevertheless, regarding claim 1, Wilson teaches a hydrochloride salt of a peptide in a pharmaceutical composition with poloxamer 188 (pg. 11, 61, 64-68, 74-75, 77, 79).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the composition comprising an INS peptide salt as suggested by Levin in view of Zhang, Moloughney, Klayko and Doyle, and combine the known prior art element of the inorganic salt hydrochloride salt of Wilson to obtain the predictable result of a pharmaceutical composition. One of ordinary skill would have been motivated to do so as taught by Wilson because the HCL salt was suitable for use in a pharmaceutical composition with a peptide and poloxamer 188 that could be administered by intramuscular injection (pg. 76, 77, 85, 87; claim 20, 31). Regarding the reasonable expectation of success, Wilson evidences a hydrochloride salt of a peptide in a pharmaceutical composition with poloxamer 188 (pg. 11, 61, 64-68, 74-75, 77, 79).
However, regarding the % wt of the poloxamer of claim 1, Levin, Zhang, Moloughney, Klayko, Doyle and Wilson are silent to a concentration of the poloxamer from 0.8% to 1 wt%.
Nevertheless, regarding claim 1, Moloughney teaches a formulation of between 1 to 10 wt% for intramuscular injection of poloxamer 188 in a pharmaceutical composition (pg. 4).
Therefore, regarding the % wt of the poloxamer of claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the composition as suggested by Levin in view of Zhang, Moloughney, Klayko, Doyle and Wilson and combine the known prior art element of poloxamer 188 of 1 to 10 wt% of Moloughney to obtain the predictable result of a pharmaceutical composition. One of ordinary skill would have been motivated to do so as taught by Moloughney because it was a suitable amount to reduce inflammation (pg. 4). Regarding the reasonable expectation of success, Moloughney evidences a formulation of between 1 to 10 wt% for intramuscular injection of poloxamer 188 in a pharmaceutical composition (pg. 4).
Notably, regarding claim 1, as stated above, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists and it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use. See M.P.E.P. §2144.05. Therefore, the taught range of 1 to 10 wt% of Moloughney, which overlaps with the claimed range, makes obvious the claimed range of 0.8 wt% to 1 wt%.
However, regarding the pH of the composition of claim 1, Levin, Zhang, Moloughney, Klayko, Doyle and Wilson are silent to the pH of the composition of between 4.5 and 6.5.
Nevertheless, regarding claim 1, Jian teaches the acceptable range is pH 2–12 for intramuscular administration of a pharmaceutical composition (pg. 827).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the composition as suggested by Levin in view of Zhang, Moloughney, Klayko, Doyle and Wilson and combine the known prior art element of a pH in the range of 2–12 of Jian to obtain the predictable result of pharmaceutical composition for intramuscular injection. One of ordinary skill would have been motivated to do so as taught by Jian because this is the known acceptable range for intramuscular injections to reduce potential irritation to the site (pg. 827). Regarding the reasonable expectation of success, Jian evidences a pH of 2-12 for pharmaceutical compositions for intramuscular administration.
Furthermore, as above, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists and it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use. See M.P.E.P. §2144.05. Therefore, the taught range of pH in the range of 2–12 of Jian makes obvious the instantly claimed range of a pH of 4.5 to 6.5.
However, regarding claim 1, although Levin teaches the composition can include the disaccharide lactose as an excipient or stabilizer (pg. 20), Levin, Zhang, Moloughney, Klayko, Doyle, Wilson, and Jain are silent to a concentration of lactose.
Nevertheless, regarding claim 1, Baheti teaches 10.7% lactose monohydrate as an excipient for intramuscular injection (table 1, 3; pg. 46, 49).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the pharmaceutical composition as suggested by Levin in view of Zhang, Moloughney, Klayko, Doyle, Wilson, and Jain, and combine the known prior art element of the 10.7% concentration of lactose monohydrate, which includes lactose of Baheti to obtain the predictable result of a pharmaceutical composition for intramuscular injection. One of ordinary skill would have been motivated to do so as taught by Baheti to achieve the maximum potency for intramuscular administration (table 3). Regarding the reasonable expectation of success, Baheti evidences 10.7% lactose as an excipient for intramuscular injection for lactose monohydrate (table 1, 3; pg. 46, 49).
Notably, regarding claim 1, as stated above, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists and It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use. See M.P.E.P. §2144.05. Therefore, the 10.7% lactose taught by Baheti , which lies within the claimed range, makes obvious the range of 8 wt% to about 12 wt% lactose of instant claims.
Regarding the wherein clause of claim 1, the wherein clause recites the conditional limitation that “when the pharmaceutical composition is diluted 10-fold in phosphate-buffered saline to prepare a solution, the solution is clear.” First, this clause recites a conditional limitation that need not occur. Therefore, because the structural limitations that set forth in the body of the claim are taught by the prior art above, the structural limitation of the claims are obvious and would meet this limitation should it occur. Furthermore, the wherein clause recites an intended use of the claimed formulation (ten-fold dilution). As stated above, the prior art teaches the structural limitation of the formulation. Therefore the pharmaceutical composition as taught by Levin in view of Zhang, Moloughney, Klayko, Doyle, Wilson, Jain and Baheti is capable of meeting the intended use. See MPEP 2111.04 which states that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”
Lastly, regarding claim 1, applicant is reminded that generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II).
Regarding claim 52, further to the discussion of claim 1 above, as stated above, Levin, Klayko, and Doyle suggest an amount of 0.8 mg/mL to 410 mg/mL of the peptide salt for an average human intramuscular dose (see claim 1 rejection above). The taught range of 0.8 mg/mL to 410 mg/mL overlaps with the claimed range of 1 is 5 mg/ml and therefore makes it obvious. As stated above (see claim 1 rejection above), where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists and differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II).
Regarding claim 53, further to the discussion of claim 1 above, as stated above, Levin, Klayko, and Doyle suggest an amount of 0.8 mg/mL to 410 mg/mL of the peptide salt for an average human intramuscular dose (see claim 1 rejection above). The taught range of 0.8 mg/mL to 410 mg/mL overlaps with the claimed range of 1 is 10 mg/ml and therefore makes it obvious. As stated above (see claim 1 rejection above), where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists and differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II).
Regarding claims 54 and 55, further to the discussion of claims 52 and 53 above, respectively, as stated above, Baheti teaches and makes obvious a lactose monohydrate concentration of 10.7% for intramuscular injection (see claim 1 rejection above). The suggested amount of 10.7% is so close to the claimed amount of 9.5% that one of ordinary skill would have expected them to have the same properties.
Applicant is directed to MPEP section 2144.05 which states a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties.").
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 27th, October, 2025, have been fully considered but are not found persuasive.
Applicant argues the previously filed declaration is commensurate in scope with amended claims (pg. 3-4).
In response, the previously filed declaration is still not commensurate in scope with instant claims because instant claims encompass the limitations of 8 to 12% lactose and a pH of 4.5 to 6.5 which are broader than the formulation that arrived at the alleged functional result.
Applicant cites the following formulations which meet the “satisfactory stability and clarity when dispersed in PBS, as evidenced from Dr. Esmira Naflali's previously submitted declaration, paragraph 11” (pg. 3-4).
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Applicant argues “Claim 1 has been amended to indicate that the identity of the saccharide as lactose, and including the amount of between 8 wt% and 12 wt%, as evidenced by the compositions in the table above as having a surprisingly improved effect” (pg. 3).
Applicant argues “the pH range of between 4.5 and 6.5 in the claims is supported by the range of the compositions in the table above” (pg. 4).
In response, Applicant is directed to MPEP 716.02(d) which states that to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
In the instant case, regarding the lactose %, the one value of 9.5% within the claimed range are not “a sufficient number of tests both inside and outside the claimed range” and therefore do not provide support for the full range.
In the instant case, regarding the pH, the two (5.67 and 5.05) pH values here within the claimed range are not “a sufficient number of tests both inside and outside the claimed range” and therefore do not provide support for the full range. Additionally, regarding pH, Applicant is directed to the art of record of Khamar et al. (WO-2002007736-A1; henceforth “Khamar”). Khamar evidences change in pH can affect the clarity of a solution (the pH of a Azithromycin solution at 5.0 is not stable and precipitates but the solution is stable and clear at a pH of 7.0; abstract).
Applicant argues “None of the cited prior art addresses any potential difficulties associated with formulating INS peptide compositions. These difficulties and the inventive elements of preparing a composition which overcomes these difficulties are demonstrated in the application as filed” (pg. 4).
In response, the claimed composition is obvious for the reasons stated above which meets instant claim limitations. As discussed further below, optimizing a pharmaceutical composition for a colorless appearance and stable formulation appear to be routine procedure and results of a particular formulation arriving at the colorless and stable conclusion are not unexpected results after routine optimization of adding particular salts and solvents. Optimizing a solution for intramuscular use, such as particular salts and solvents, appears to be within the level of one of ordinary skill at least based on the art Khamar et al. (WO-2002007736-A1; henceforth “Khamar”), discussed further below, which evidence optimization of a clear pharmaceutical composition (see also MPEP 2144.05 (II) for discussion on routine optimization).
Applicant argues “the claimed compositions, as demonstrated in the application, have surprisingly advantageous characteristics which include an improved solubility of pharmaceutical compositions especially when re-dispersed in PBS” (pg. 4).
In response, as discussed above, the alleged unexpected result is not commensurate in scope with instant claims for the reasons stated above.
Additionally, as previously stated, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art (“improved solubility of pharmaceutical compositions especially when re-dispersed in PBS”) cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Furthermore, as stated in the previous office action (pg. 15), Applicant is directed to the art of Khamar et al. (WO-2002007736-A1; henceforth “Khamar”). Khamar evidences it desirable to optimized pharmaceutical compositions to achieve a clear composition for injection (“It is desirable to have a clear liquid formulation” abstract). Khamar evidences optimization to this effect by changing the pH of the solution, adding particular salts and solvents (abstract). Therefore, optimizing a pharmaceutical composition for a colorless appearance and stable formulation is routine procedure and results of a particular formulation arriving at the colorless and stable conclusion are not unexpected results after routine optimization of adding particular salts and solvents (abstract).
Conclusion
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.
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632