FINAL 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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/13/2026 has been considered by the examiner and initialed copies of the IDS are included with the mailing of this office action.
Status of the Claims
This action is in response to papers filed 01/13/2026 in which claims 1-19, 25, and 28 were canceled; and claims 20-21, 23, 39-41, and 43 were amended. All the amendments have been thoroughly reviewed and entered.
Claims 20-24, 26-27, and 29-45 are under examination.
Withdrawn Objection/Rejection
The Examiner has re-weighted all the evidence of record. Any rejection and/or objection not specifically addressed below is hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Maintained Rejection
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.
Claim(s) 20-24, 26-27, and 29-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hampson et al (US 2016/0271132 A1) in view of Dhingra et al (US 2018/0021349 A1) and Patel et al (Drug Delivery, 2016, 23(8): 3027-3042).
Regarding claims 20 and 21, Hampson teaches a method for treating cancer or benign proliferative disorders comprising administering a therapeutically effective amount of a pharmaceutical composition comprising lopinavir (Abstract; [0001], [0013]-[0014], [0042]-[0045]; claim 33). Hampson also teaches a method of treating a patient having an HPV related dysplasia of the cervix comprising administering to said patent a therapeutically effective does of the pharmaceutical composition comprising lopinavir (Abstract; [0001], [0014], [0042]-[0045]; claim 23). Hampson teaches the pharmaceutical composition is administered intra-vaginally or orally ([0054]-[0055], [0057]-[0058], [0064]-[0067], [0083], [0084], [0088]; claim 23). Hampson teaches the pharmaceutical composition is the form of an emulsion containing oleic acid and emulsifiers ([0081]-[0082]).
However, Hampson does not teach the emulsifiers being at least two emulsifiers comprise at least a first emulsifier which has a HLB value greater than about 14 and at least a second emulsifier which has a HLB value less than about 6; and wherein the total emulsifier content is less than 30% by weight of the total composition, of claim 20 and 21.
Regarding the at least two emulsifiers and total emulsifier content is less than 30% by weight of the total composition of claims 20 and 21, Dhingra teaches an emulsion formulation in the form of a self-emulsifying drug delivery system (SEDDS) comprising a therapeutic agent that is poorly water soluble and has poorly fast state bioavailability, at least one hydrophilic surfactant, at least one lipophilic surfactant, and a fatty acid such as oleic acid (Abstract; [0003]-[0012], [0031]-[0033], [0062]-[0069], [0091]-[0129], [0141]-[0151]. [0193]-[0216]; claims 1-17]). Dhingra teaches the at least one hydrophilic surfactant has an HLB greater than 10 and the at least one lipophilic surfactant has HLB less than 5 ([0105] and [0108]). Dhingra teaches the at least one hydrophilic surfactant include Cremophor RH40 and at least one lipophilic surfactant include glycerol monooleate (Maisine 35-1) ([0035]-[0036], [0105], [0108], [0123], [129], [0200], [0210], [0212], [0214]; claims 12, 16 and 17). As evidenced by the instant specification, Cremophor RH40 is defined as an emulsifier having an HLB of 14-16, and glycerol monooleate (Maisine 35-1) is defined as an emulsifier having a HLB of 4 (Specification, Table of page 11). Dhingra teaches the emulsion formulation contains 5% -37.5% by weight of the at least one hydrophilic surfactant and 15% - 65% by weight of the at least one lipophilic surfactant ([0034]-[0035], [0116]-[0118]; claim 5).
It would have been obvious to one of ordinary skill in the art to incorporate the SEDDS comprising at least one hydrophilic surfactant, at least one lipophilic surfactant, and a fatty acid such as oleic acid, as the emulsion used in the method of Hampson, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because as discussed above, Hampson indicated that lopinavir can be formulated in a pharmaceutical composition such as an emulsion containing emulsifiers and oleic acid, and per Patel, it is well-established in the prior art, lopinavir shows poor bioavailability because of poor aqueous solubility and extensive hepatic first-pass metabolism, and thus would benefit from formulating in a self-emulsifying drug delivery system to improve dissolution rate and bioavailability of lopinavir (Patel: Abstract; Introduction; pages 3028, 3032-3033 and 3039-3040). Given that Dhingra teaches the benefit of SEDDS as providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of the therapeutic agent, as well as, higher bioavailability of the therapeutic agent, an ordinary artisan would have looked to formulating lopinavir in a emulsion formulation such as an SEDDS comprising at least one hydrophilic surfactant, at least one lipophilic surfactant, and a fatty acid such as oleic acid of Dhingra with a reasonable expectation of improving dissolution rate and bioavailability of lopinavir for effective treatment of cancer, benign proliferative disorders, or an HPV related dysplasia of the cervix.
It would also have been obvious to one of ordinary skill in the art routinely optimize the total emulsifier content to an amount of less than 30% by weight of the total composition, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because as discussed above, Dhingra teaches the emulsion formulation can be optimized to contain 5% - 37.5% by weight of the at least one hydrophilic surfactant and 15% - 65% by weight of the at least one lipophilic surfactant, which are parameters that overlaps the claimed total emulsifier content range of less than 30% by weight of the total composition. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the total emulsifier content in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claims 22 and 26, Hampson teaches the pharmaceutical composition reduces the severity of the HPV related dysplasia ([0038], [0093], [0095]; claim 24).
Regarding claim 23, Hampson teaches the pharmaceutical composition of induces apoptosis of HPV infected cells ([0105], [0224]; claim 32).
Regarding claim 24, Hampson teaches Hampson teaches the patient has the patient has a cervical cytology of high grade squamous intraepithelial lesion (HSIL), atypical squamous cells of undetermined significance (ASCUS), or low grade squamous intraepithelial lesion (LSIL) ([0019], [0036], [0045], [0048]-[0049], [0092] and [0094]; claim 27).
Regarding claim 27, Dhingra teaches the lipophilic surfactant is glycerol monooleate (Maisine 35-1) ([0035], [0104], [0114]; claims 13 and 17).
Regarding claim 29, as discussed above, Hampson and Dhingra teaches the emulsion formulation contains oleic acid.
Regarding claims 30 and 31, Hampson teaches the hydrophilic surfactant includes polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 ([0108], [0201], [0210]; claim 7). As evidenced by the instant specification, polysorbate 80 is defined as a emulsifier having an HLB of 15 (Specification, Table on page 11).
Regarding claims 32 and 33, as discussed above, Dhingra teaches the lipophilic surfactant includes glycerol monooleate (Maisine 35-1). As evidenced by the instant specification glycerol monooleate (Maisine 35-1) is defined as an emulsifier having a HLB of 4 (Specification, Table on page 11).
Regarding claim 34, Dhingra teaches the emulsion formulation contains 5% -37.5% by weight of the at least one hydrophilic surfactant and 15% - 65% by weight of the at least one lipophilic surfactant ([0034]-[0035], [0116]-[0118]; claim 5), which overlaps the claimed ratio of between about 1:10 and about 10:1. The courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of weight ratio of between first and second emulsifiers would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 35, Dhingra teaches the hydrophilic surfactant can be a mixtures of two hydrophilic surfactants ([0108], [0201], [0210]; claim 7).
Regarding claim 36, as discussed above, Dhingra teaches the at least one hydrophilic surfactant include Cremophor RH40 and at least one lipophilic surfactant include glycerol monooleate (Maisine 35-1) ([0035]-[0036], [0105], [0108], [0123], [129], [0200], [0210], [0212], [0214]; claims 12, 16 and 17). As evidenced by the instant specification, Cremophor RH40 is defined as an emulsifier having an HLB of 14-16, and glycerol monooleate (Maisine 35-1) is defined as an emulsifier having a HLB of 4 (Specification, Table on page 11). Dhingra teaches the hydrophilic surfactant can be a mixtures of two hydrophilic surfactants including Cremophor RH40 and polysorbate 80 ([0210]). Dhingra teaches the emulsion formulation contains 5% -37.5% by weight of the at least one hydrophilic surfactant and 15% - 65% by weight of the at least one lipophilic surfactant ([0034]-[0035], [0116]-[0118]; claim 5), which overlaps the claimed total emulsifiers content is less than 30% by weight of the total pharmaceutical composition. As discussed above, the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of total emulsifier content in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 37, as discussed above, Dhingra teaches at least one hydrophilic surfactant include Cremophor RH40 (a polyoxyl castor oil derivative).
Regarding claims 38, as discussed above, Dhingra teaches the emulsion formulation contains 5% -37.5% by weight of the at least one hydrophilic surfactant and 15% - 65% by weight of the at least one lipophilic surfactant, which overlaps the claimed total emulsifiers content is less than 25% by weight of the total pharmaceutical composition. As discussed above, the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of total emulsifier content in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claims 39-41, as discussed above, Dhingra teaches the emulsion formulation contains 5% -37.5% by weight of the at least one hydrophilic surfactant and 15% - 65% by weight of the at least one lipophilic surfactant, which overlaps the claimed parameters for first emulsifier, second emulsifier and third emulsifier of claims 39-41, respectively. As discussed above, the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of weight amount of first emulsifier, second emulsifier and third emulsifier in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 42, Hampson teaches the pharmaceutical composition further contains ritonavir (Abstract; [0001], [0013]-[0014], [0042]-[0045]; claims 16, 23, and 33).
Regarding claim 43, Hampson teaches the weight ratio of lopinavir to ritonavir include from about 1:10 to about 10:1 ([0068]-[0079]), which overlaps the claimed “between about 1:10 and about 18:1. As discussed above, the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of weight ratio of lopinavir to ritonavir in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 44, Dhingra teaches the emulsion formulation encapsulated within a capsule ([0013], [0124], [0137]-[0138]).
Regarding claim 45, Dhingra teaches the hydrophilic surfactant includes Cremophor EL-35 (PEG 35 castor oil) ([0035]-[0037] and [0201]).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 01/13/2026 have been fully considered but they are not persuasive.
Applicant argues:
“None of the cited art references, alone or in combination teach or suggest the claimed invention. As acknowledged by the Office, Hampson does not teach or suggest a composition comprising at least two emulsifiers, as claimed. The instant invention is based on the surprising discovery that "when at least two emulsifiers with particular properties are combined with an unsaturated free fatty acid and at least one active pharmaceutical ingredient (lopinavir), then a SEDDS formulation is obtained having unexpectedly good properties (e.g., drug dissolution and therefore potentially superior bioavailability properties) even though the formulations contain relatively low total emulsifier contents." See Specification at [0005], emphasis added.” (Remarks page 8, 1st paragraph).
In response, the Examiner disagrees. The 103 rejection is based on the combined teachings of Hampson, Dhingra, and Patel. As discussed above in the standing 103 rejection, Dhingra teaches the claimed at least two emulsifiers and provide the guidance for incorporating the SEDDS comprising at least one hydrophilic surfactant, at least one lipophilic surfactant, and a fatty acid such as oleic acid as the emulsion used in the method of Hampson, and Patel provided the motivation and reasonable expectation of success in doing so by establishing that it is known in the prior art that lopinavir shows poor bioavailability because of poor aqueous solubility and extensive hepatic first-pass metabolism, and thus would benefit from formulating in a self-emulsifying drug delivery system to improve dissolution rate and bioavailability of lopinavir. Thus, as discussed above in the standing 103 rejection, given that Dhingra teaches the benefit of SEDDS as providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of the therapeutic agent, as well as, higher bioavailability of the therapeutic agent, an ordinary artisan would have looked to formulating lopinavir in a emulsion formulation such as an SEDDS comprising at least one hydrophilic surfactant, at least one lipophilic surfactant, and a fatty acid such as oleic acid of Dhingra with a reasonable expectation of improving dissolution rate and bioavailability of lopinavir for effective treatment of cancer, benign proliferative disorders, or an HPV related dysplasia of the cervix.
As such, Applicant’s alleged advantage of using SEDDS formulation for good properties of drug dissolution and superior bioavailability is not unexpected, but rather expected properties that are well-established by the teachings from Dhingra and Patel supra.
Applicant argues:
“there would be no motivation to combine and/or modify the teachings of Hampson with Dhingra and/or Patel. Dhingra relates to compositions for treating "testosterone deficiency." See Dhingra at [0002]. The molecular pathways of Dhingra and Hampson are entirely distinct.” (Remarks, page 8, 2nd paragraph).
In response, the Examiner disagrees. Dhingra is drawn to and used for teaching SEDDS formulation for drug delivery of a therapeutic agent that is poorly water soluble and has poorly fast state bioavailability, providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of the therapeutic agent. See 103 rejection, pages 4-6 of this office action. Lopinavir used in the claimed method is a therapeutic agent that is known to be poorly water soluble and has poorly fast state bioavailability.
As discussed above, Patel established that lopinavir shows poor bioavailability because of poor aqueous solubility and extensive hepatic first-pass metabolism, and thus would benefit from formulating in a self-emulsifying drug delivery system to improve dissolution rate and bioavailability of lopinavir.
Accordingly, the combined teachings of Hampson, Dhingra, and Patel are proper to render obvious Applicant’s claimed method.
Applicant argues:
“[i]n order to arrive at the claimed invention, a person skilled in the art would have to take the self-emulsifying composition of Dhingra and incorporate the active agent from Hampson (lopinavir) into the composition, and have a reasonable expectation that such a composition would be used for "treating and/or inhibiting the development or progression of cancers and benign proliferative disorders" (claim 20) or "treating a patient having HPV related dysplasia of the cervix" (claim 21). There are simply too many modifications of the cited art to arrive at the claimed invention. As described in the instant specification, the claimed composition provides unexpectedly good properties ( [0003]), especially when used with a pharmaceutical agent (lopinavir) that is prone to degradation ([0006]), and that the composition has good API dissolution profiles, with a low total emulsifier content ( [0070]), which is not disclosed in the cited art, alone or in combination.” (Remarks, page 8, 3rd paragraph).
In response, the Examiner disagrees. Lopinavir is known to be used for treating and/or inhibiting the development or progression of cancers and benign proliferative disorders per Hampson. See 103 rejection, pages 3-4 of this office action. Hampson also teaches that lopinavir is suitable for formulation in an emulsion. See 103 rejection, page 4 of this office action.
As discussed above, Dhingra is drawn to and used for teaching SEDDS formulation for drug delivery of a therapeutic agent that is poorly water soluble and has poorly fast state bioavailability, providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of the therapeutic agent. See 103 rejection, pages 4-6 of this office action. Lopinivar used in the claimed method is a therapeutic agent that is known to be poorly water soluble and has poorly fast state bioavailability.
As discussed above, Patel established that lopinavir shows poor bioavailability because of poor aqueous solubility and extensive hepatic first-pass metabolism, and thus would benefit from formulating in a self-emulsifying drug delivery system to improve dissolution rate and bioavailability of lopinavir.
Thus, as discussed above in the pending 103 rejection, given that Dhingra teaches the benefit of SEDDS as providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of the therapeutic agent, as well as, higher bioavailability of the therapeutic agent, an ordinary artisan would have looked to formulating lopinavir in a emulsion formulation such as an SEDDS comprising at least one hydrophilic surfactant, at least one lipophilic surfactant, and a fatty acid such as oleic acid of Dhingra with a reasonable expectation of improving dissolution rate and bioavailability of lopinavir for effective treatment of cancer, benign proliferative disorders, or an HPV related dysplasia of the cervix.
As such, Applicant’s alleged advantage of using SEDDS formulation for good properties of drug dissolution and superior bioavailability is not unexpected, but rather expected properties that are well-established by the teachings from Dhingra and Patel supra. It is noted that "[e]xpected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967)
Accordingly, the combined teachings of Hampson, Dhingra, and Patel are proper to render obvious Applicant’s claimed method.
As a result, for at least reasons discussed above, claims 20-24, 26-27, and 29-45 remain rejected as being obvious and unpatentable over the combined teachings of Hampson, Dhingra, and Patel, in the standing 103 rejection as set forth in this office action.
Conclusion
No claim is allowed.
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.
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/DOAN T PHAN/ Primary Examiner, Art Unit 1613
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