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 arguments, filed 11/07/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Applicant elected, without traverse, species “mono-O-(5,9,13,17-tetramethyloctadec-4- enoyl)sorbitan” as a single amphipathic compound; substituents of: X and Y together denote an oxygen atom, n denotes the integer 2, m denotes the integer 2, one double bond and three single bonds, and R denotes a hydrophilic group generated from sorbitan; and soybean phosphatidylcholine of claim 7, in the reply filed on 05/21/2025.
Response to Arguments
Applicant asserts Tabata or Ikeda alone does not teach or suggest the adhesion preventing agent comprising a phospholipid and wherein the weight ratio between the amphipathic compound and the phospholipid is 50:50 to 20:80, as required by Applicant's amended, independent claim 1 and its dependent claims.
The Examiner does not find the argument persuasive. As this is a 103 obviousness rejection, no one piece of prior art is required to teach each and every claim limitation. As discussed in the rejection, Johnsson provides motivation to incorporate a phospholipid into the composition of Tabata or Ikeda. See MPEP 2141(III).
Applicant mainly asserts Johnsson does not teach or suggest a combination of the "amphipathic compound of general formula (I)" and a phospholipid, nor the weight ratio between the "amphipathic compound of general formula (I)" and the phospholipid. In Johnsson, the amount of phosphatidyl choline (component "a") of 5-90 wt. % is specified as being combined with component "b" and component "c", and the component "b" and component "c" are not an amphipathic compound of general formula (I) as defined by Applicant's amended, independent claim 1 (nor of Tabata or Ikeda). Therefore, the amount of phosphatidyl choline (component "a") of 5-90 wt. % does not overlap with the weight ratio between the amphipathic compound and the phospholipid is 50:50 to 20:80 as defined by Applicant's amended, independent claim 1.
The Examiner does not find the argument persuasive. As this is a 103 obviousness rejection, no one piece of prior art is required to teach each and every claim limitation. As discussed in the rejection, Tabata or Ikeda each provides the amphipathic compound. See MPEP 2141(III). Moreover, as discussed in the rejection above, Tabata or Ikeda each discloses amounts of amphipathic compound (i.e. 1-80 wt. % of Tabata, and 0.1-90% by mass of Ikeda). Johnsson discloses wherein a phosphatidyl choline component is suitably 5-90 wt. %. Accordingly, it would have been obvious to one of ordinary skill in the art to have selected an amount of amphipathic compound from the ranges disclosed by Tabata or Ikeda, and an amount of phosphatidyl choline from the range disclosed by Johnsson. Such amounts selected would have equated to a weight ratio that overlaps with the instantly claimed ratio of amphipathic compound : phospholipid, thus making the claimed ratio obvious. As such, the argument is unpersuasive.
Applicant mainly asserts on pages 14-15 of the Remarks that Johnsson merely discusses a specific combination of the "non-toxic" at least 3 amphiphilic components as seen in the Examples is used as a stable, non-toxic non-lamellar dispersion. Johnsson does not teach or suggest whatsoever that a phosphatidyl choline (PC) can be used with the amphiphilic component of the general formula (I) of Tabata or Ikeda, for remarkably improving stability and toxicity. Therefore, a person skilled in the art would not be motivated to combine PC with an amphiphilic component other than "a diacyl glycerol (DAG), a tocopherol, or a diacyl phosphatidyl ethanolamine (PE) component, or mixtures thereof' and "a non-ionic stabilising component", in particular the amphiphilic component of the general formula (I), to provide remarkably high stability and remarkably low toxicity, with reasonable expectation of success.
The Examiner disagrees. As discussed above, it is not necessary for Johnsson to disclose a specific amphipathic compound as instantly claimed (MPEP § 2141(III)). Tabata, or alternatively Ikeda, each discloses non-lamellar formulations comprising amphipathic compounds and inclusion of additional ingredients suitable for pharmaceutical formulations. Johnsson discloses non-lamellar pharmaceutical formulations comprising at least one amphiphile and at least one phosphatidyl choline component that displays high stability and low toxicity. Thus one of ordinary skill in the art would reasonably expect the phosphatidyl choline component of Johnsson to contribute to said stability and toxicity.
Moreover, as supported in MPEP § 2123, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art and is not limited to preferred embodiments and working examples. Therefore the disclosure of Johnsson is not limited to the examples of Johnsson. As such, even if, purely arguendo, Johnsson were to be interpreted as not explicitly teaching or at least suggesting the phosphatidyl choline component contributes to stability and low toxicity, it still would have been obvious for one of ordinary skill in the art to have included a phosphatidyl choline component in the formulation of Tabata or Ikeda, since such component is a known and effective ingredient suitable for pharmaceutical formulations comprising amphiphilic compounds as taught by Johnsson. As such, the argument is unpersuasive.
Applicant mainly asserts Hwang does not teach nor suggest how to make an amphipathic compound of the general formula (I) as defined by Applicant's independent claim 21 and its dependent claims, having a hydrophilic group derived from sorbitan. Further, Hwang does not teach nor suggest whether the modified amphipathic compound of the general formula (I) having the hydrophilic group from sorbitan, as defined by Applicant's independent claim 21, can form into liquid crystals and can be combined with a phospholipid to prepare a composition having in vivo high safety. The Examiner does not submit any evidence or reason indicating that a person skilled in the art would readily produce the modified amphipathic compound expect whether it provides a high safety when administered together with a phospholipid. Thus, a person skilled in the art would not have readily arrived at the modified amphipathic compound of claims 21-23 with a reasonable expectation of success.
The Examiner does not find the argument persuasive. As discussed in detail above and supported by MPEP § 2141 (III), it is not necessary for Hwang to disclose each and every claim limitation. In this instant case, Ikeda discloses the general formula of the amphipathic compound. Furthermore, the Examiner’s rationale need not be the same as Applicant’s to establish obviousness, and it is not necessary for the prior art to suggest the combination to achieve the same advantage or result discovered by Applicant. See MPEP § 2144 (IV). As such, Applicant’s argument is unpersuasive.
Applicant mainly asserts the addition of phospholipid at a given amount or more to the amphipathic compound having an isoprenoid fatty acid chain (an isoprenoid lipid) improves safety during in vivo administration regardless of dosage forms (see, e.g., paragraph [0197]) and a certain amount or more of the phospholipid, not the oil, relative to the isoprenoid lipid was found to be necessary for securing an in vivo safety (see, e.g., paragraph [0243]).
The Examiner does not find the argument persuasive. Regarding allegations of unexpected results, Applicant has the burden of explaining the data in any declaration they proffer as evidence of non-obviousness. See MPEP § 716.02(b)(II). Applicant has explained that various statements referenced in the specification support their position, but these cannot take the place of evidence in the record. See MPEP § 716.01(c)(II).
Moreover, any differences between the claimed invention and the prior art may be expected to result in some difference in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. The burden is on Applicant to establish that the results are in fact really unexpected and of statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992). See also MPEP § 716.02. Applicant does not appear to have discussed same with respect to objective data.
It is noted that such objective data may have been presented at the examples of pages 54-74 and 79-84 of the instant Specification, but Applicant should discuss them specifically. For example, it is not clear to the Examiner how the weight ratio of isoprenoid lipid : phospholipid improves safety during in vivo administration as asserted by Applicant. For example, para. [0242] of the Specification (as referenced by the Applicant on p. 17 of the Remarks) asserts wherein Table 9, formulation No. 127 developed abscess, whereas formulation No. 128 did not. However, formulation Nos. 127 and 128 both have the same isoprenoid lipid : phospholipid weight ratio as formulation (80:20 SPC).
Finally, assuming purely arguendo that the unexpectedness of the results have been established, the probative value of the evidence as compared to the invention as claimed must then be determined, i.e., the claims must be “commensurate in scope” with the showing. MPEP § 716.02(d). See also MPEP § 2145. The examples of pages 54-74 and 79-84 employ specific components in specific percentages, and even if Applicant were to show unexpected results, they would be have been obtained, for example, not with the broad class of “an amphipathic compound represented by the general formula (I)” generally, but instead with specific species. Note for example, [0242] of the instant specification specifies C22 pentaerythritol ester and C22 sorbitan ester as the amphipathic lipid. Applicant would need to explain how these specific species are “reasonably representative” of the more broadly claimed subject matter of the claims.
Claim Rejections - 35 USC § 103 (maintained)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-9, 11-16 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Tabata et al. (US 2016/0067208 A1, 03/10/2016, IDS reference) (hereinafter Tabata) in view of Johnsson et al. (US 2008/0274176 A1, 11/06/2008) (hereinafter Johnsson).
Tabata discloses an adhesion preventing agent comprising a mixture of the at least one amphipathic compound, an aqueous medium, and at least one liquid carrier including oil, ester, alcohol, and a physiologically acceptable organic solvent ([0205]). The amphipathic compounds (i.e. saturated/unsaturated fatty-acid ester/ethers) have a general formula (I),
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,
wherein X and Y each denotes a hydrogen atom or together denote an oxygen atom; n denotes an integer from 0 to 2; m denotes the integer 1 or 2; AA (
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) denotes a single bond or double bond; and R denotes a hydrophilic group having two or more hydroxyl groups (abs), including those generated by removal of one hydroxyl group from glycerol ([0020]). The amphipathic compounds may be included in an amount of 1-80% of the total amount of the adhesion preventing agent ([0199]). The adhesion preventing agent may further comprise additives including stabilizer, buffering agent and preservative that are pharmaceutically commonly used ([0210]), and produced in various dosage forms including aerosol agent, spray agent, topical formulation, or injection ([0211]). Exemplary amphipathic compounds include mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol ([0146]).
Tabata differs from the instant claims insofar as not explicitly disclosing wherein the adhesion preventing agent comprises a phospholipid.
However, Johnsson discloses stable non-lamellar amphiphile-containing compositions comprising 5-90 wt. % of a phosphatidyl choline component ([0017]), which is particularly advantageous component in that it is widely and readily available and can conveniently be purified from a variety of natural sources ([0027]) such as soy ([0028]), and maintains remarkably high stability and remarkably low toxicity of the compositions ([0029]). The compositions further comprise active agents including peptide/protein actives such as gonadorelin and derivatives (e.g., leuprolide) ([0051]).
Accordingly, it would have been obvious to one of ordinary skill in the art to have included 5-90 wt. % of a phosphatidyl choline, from a natural source such as soy, in the adhesion preventing agent of Tabata, since it is a known and effective component capable of contributing to stability and low toxicity in non-lamellar amphiphile-containing compositions as taught by Johnsson.
Regarding claims 1, 4 and 5, it would have been obvious to one of ordinary skill in the art to have selected an amount of phosphatidyl choline from the disclosed range of 5-90 wt. %, such that the amounts selected would have equated to a ratio that overlaps with the instantly claimed ratio of amphipathic compound : phospholipid, thus making the claimed ratio obvious.
Regarding claim 13, Tabata further discloses wherein the adhesion preventing agent may be in the form of emulsion ([0514]).
Regarding claim 14, Tabata further discloses wherein the amphipathic compound is a liquid crystal compound and capable of forming a non-lamellar liquid crystal in an aqueous medium ([0160]).
Claims 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Tabata et al. (US 2016/0067208 A1, 03/10/2016, IDS reference) (hereinafter Tabata) in view of Johnsson et al. (US 2008/0274176 A1, 11/06/2008) (hereinafter Johnson), further in view of Hwang et al. (US 2015/0374850 A1, 12/31/2015) (hereinafter Hwang).
The combination of Tabata and Johnsson is discussed in detail above, but do not specify wherein the hydrophilic group is sorbitan.
However, Hwang discloses compositions which forms into liquid crystals in an aqueous fluid including a liquid crystal forming material ([0001]) that may be a sorbitan unsaturated fatty acid ester which has at least two hydroxyl groups in the polar head group ([0028]).
Tabata discloses wherein the hydrophilic group has two or more hydroxyl groups. Accordingly, it would have been obvious to one of ordinary skill in the art to have formulated the composition of Tabata with sorbitan as the hydrophilic group, since it is a known and effective group containing at least two hydroxyl groups suitable for compositions forming liquid crystals in an aqueous fluid as taught by Hwang.
Claims 1-9 and 11-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ikeda (US 2012/0264923 A1, 10/18/2012, IDS reference) in view of Johnsson et al. (US 2008/0274176 A1, 11/06/2008) (hereinafter Johnson).
Ikeda discloses an injectable amphipathic compound that forms non-lamellar liquid crystals in an aqueous solvent and can retain a drug as a base for an injection formulation ([0066]). The amphipathic compound have the general formula (I):
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,useful as a drug delivery carrier in an aqueous medium ([0014]), wherein one molecule of long chain unsaturated hydrocarbon is bound via an ether or ester bond to one molecule of polyhydric alcohol ([0241]). An embodiment includes wherein X and Y each denotes a hydrogen atom or together denote an oxygen atom; n denotes an integer from 0 to 2; m denotes 1 or 2; and R denotes a hydrophilic group generated by removal of one hydroxyl group from glycerol (abs). An exemplary amphipathic compound may be mono-O-(5,9,13,17-tetramethyloctadec-4-enoyl)glycerol ([0018]). The base for injection formulations possesses sustained drug release property, and particularly depot formulations ([0287]). Suitable drugs includes a peptide, a protein, and a low-molecular-weight-drug ([0286]). The amphipathic compound may be included at a concentration ranging from 0.1-90% by mass ([0269]). The base for injection formulation may further contain one or more carriers, excipients, or inactive additives (e.g., preservatives). The aqueous media may include water-soluble organic substances such as glycerin, ethylene glycol, and ethanol ([0288]), and may also contain surfactants ([0267]).
As noted by para. [0087] of the instant Specification, alcohols such as ethanol is an organic solvent. Thus the water-soluble organic substance of Ikeda meets the limitation of organic solvent as claimed.
Ikeda differs from the instant claim insofar as not explicitly disclosing wherein the formulation comprises a phospholipid.
However, Johnsson discloses stable non-lamellar amphiphile-containing compositions comprising 5-90 wt. % of a phosphatidyl choline component ([0017]), which is particularly advantageous component in that it is widely and readily available and can conveniently be purified from a variety of natural sources ([0027]) such as soy ([0028]), and maintains remarkably high stability and remarkably low toxicity of the compositions ([0029]). The compositions further comprise active agents including peptide/protein actives such as gonadorelin and derivatives (e.g., leuprolide) ([0051]).
Accordingly, it would have been obvious to one of ordinary skill in the art to have included 5-90 wt. % of a phosphatidyl choline, from a natural source such as soy, in the formulation of Ikeda, since it is a known and effective component capable of contributing to stability and low toxicity in non-lamellar amphiphile-containing compositions as taught by Johnsson.
Regarding claims 1, 4 and 5, it would have been obvious to one of ordinary skill in the art to have selected an amount of phosphatidyl choline from the disclosed range of 5-90 wt. %, such that the amount selected would have equated to a ratio that overlaps with the instantly claimed ratio of amphipathic compound : phospholipid, thus making the claimed ratio obvious.
Regarding claims 18 and 19, it would have been obvious to one of ordinary skill in the art to have included a drug such as leuprolide in the formulation of Ikeda, since it is a known and effective drug suitable for delivery in a non-lamellar amphiphile-containing composition as taught by Johnsson.
Regarding claim 13, Ikeda further discloses wherein the amphipathic compound may form an emulsion ([0284]).
Regarding claim 16 reciting in the preamble wherein the composition is for adhesion prevention of living tissue, this is merely a recitation of the intended use of the composition. Since the composition of the prior art comprises substantially the same active ingredients as the claimed composition, the composition of the prior art would be usable to prevent adhesion of living tissue, whether the prior art recognizes such use or not.
Claims 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Ikeda (US 2012/0264923 A1, 10/18/2012, IDS reference) in view of Johnsson et al. (US 2008/0274176 A1, 11/06/2008) (hereinafter Johnson), further in view of Hwang et al. (US 2015/0374850 A1, 12/31/2015) (hereinafter Hwang).
The combination of Ikeda and Johnsson is discussed in detail above, but do not specify wherein the hydrophilic group is sorbitan.
However, Hwang discloses compositions which forms into liquid crystals in an aqueous fluid including a liquid crystal forming material ([0001]) that may be a sorbitan unsaturated fatty acid ester which has at least two hydroxyl groups in the polar head group ([0028]).
Ikeda discloses wherein one molecule of long chain unsaturated hydrocarbon is bound via an ether or ester bond to one molecule of polyhydric alcohol. Accordingly, it would have been obvious to one of ordinary skill in the art to have formulated the formulation of Ikeda with sorbitan as the R group, since it is a known and effective group comprising at least two hydroxyl groups (i.e. polyhydric alcohol) suitable for compositions forming liquid crystals in an aqueous fluid as taught by Hwang.
Double Patenting (maintained)
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 1-9 and 11-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,296,014 in view of Johnsson et al. (US 2008/0274176 A1, 11/06/2008) (hereinafter Johnson). The patented claims differ from the pending claims insofar as not disclosing a phospholipid or a weight ratio of the amphipathic compound : phospholipid. However, Johnsson discloses stable non-lamellar amphiphile-containing compositions comprising 5-90 wt. % of a phosphatidyl choline component ([0017]), which is particularly advantageous component in that it is widely and readily available and can conveniently be purified from a variety of natural sources ([0027]) such as soy ([0028]), and maintains remarkably high stability and remarkably low toxicity of the compositions ([0029]). Accordingly, it would have been obvious to one of ordinary skill in the art to have included 5-90 wt. % of a phosphatidyl choline, from a natural source such as soy, in the preparation of the patented claims, since it is a known and effective component capable of contributing to stability and low toxicity in non-lamellar amphiphile-containing compositions as taught by Johnsson. Regarding the amount of amphipathic compound in the weight ratio, although the patented claims do not explicitly disclose an amount of the amphipathic compound, it would have taken no more than the relative skills of one of ordinary skill in the art to have arrived at the claimed weight ratio amount depending on the therapeutic effects desired. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See MPEP § 2144.05(II)(A).
Response to Arguments
Applicant asserts Johnsson does not teach or suggest a combination of, or the weight ratio between, the “amphipathic compound of general formula (I)” and a phospholipid.
As discussed in the rejection above, as this is an obviousness rejection, it is not necessary for Johnsson to disclose each and every claim limitation. As such, Applicant’s argument is unpersuasive. Regarding the weight ratio, the argument has been addressed while addressing Johnsson as discussed above.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUCY TIEN whose telephone number is (571)272-8267. The examiner can normally be reached Monday - Thursday 8:30 AM - 6:30 PM EST.
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/LUCY M TIEN/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612