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 .
DETAILED ACTION
Election/Restrictions
Applicant elected without traverse of following species in the reply filed on 10/30/2025:
Hydrophilic surfactant: polyoxyl 40 hydrogenated castor oil;
Hydrophobic surfactant: propylene glycol monolaurate;
Phytosterol ester: ester of ß-sitosterol;
Solubilizer: dl-alpha-tocopherol;
Subject: has been treated with an anti-hypertensive therapy.
Claims 1-3, 5-11, 25, 29, 30, 33, 38, 40, 41, 46, and 54 read on the elected species.
Claim 50 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected invention/species.
Status of Claims
Claims 1-3, 5-11, 25, 29, 30, 33, 38, 40, 41, 46, 50 and 54 are pending in the present application. Claim 50 is withdrawn.
Claims 1-3, 5-11, 25, 29, 30, 33, 38, 40, 41, 46, and 54 are under examination in this office action.
Priority
The instant application 18/201,498 filed on 05/24/2023, is a continuation of PCT/US2022/029819 filed on 05/18/2022, which claims priority benefit of US provisional application No. 63/190,609 filed on 05/19/2021.
Information Disclosure Statement
The information disclosure statements are in compliance with the provisions of 37 CFR1.97. Accordingly, the reference listed in IDS are being considered by the Examiner. Reference written in foreign language is considered to the degree of English abstract or patent family of foreign patent by Examiner. It is noted that Applicant has submitted an information disclosure statement with over 25 pages of references. While the Examiner has made every effort to thoroughly review these references, one could have very well missed a pertinent document.
Claim Objections
Claims 1, 6-9, 33, and 54 are objected to because of the following informalities:
Claims 1, 6-9, 33 and 54 recite multiple “Serum Value” of testosterone that should be in lowercase.
Claim Interpretation
Instant claims are directed to a method of treating testosterone deficiency in a subject in need thereof, comprising a series of steps: a) performing a treatment regimen comprising orally administering to the subject 400 mg of testosterone undecanoate (TU) daily with a meal, wherein the TU is administered in a pharmaceutical composition comprising TU, a non-sterol solubilizing agent effective for solubilization of the TU, and a phytosterol or phytosterol ester; b) establishing a first steady state serum concentration of testosterone; c) following step (b), providing a first steady state Serum Value of testosterone in the subject that is measured from about 3 hours to about 6 hours after administration of the pharmaceutical composition; and d) performing a first titration of the testosterone undecanoate,
wherein: i) if the first Serum Value of testosterone is less than about 400/F + b ng/dL, then orally administering to the subject about 600 mg TU daily to establish a second steady state Serum Value of testosterone that is higher than the first steady state Serum Value of testosterone; ii) if the first Serum Value of testosterone is from about 400/F + b ng/dL to about 900/F + b ng/dL, then continuing to orally administer to the subject about 400 mg TU daily to maintain the first steady state Serum Value of testosterone; or iii) if the first Serum Value of testosterone is greater than about 900/F + b ng/dL, then orally administering to the subject about 200 mg TU daily to establish a second steady state Serum Value of testosterone that is lower than the first steady state Serum Value of testosterone.
Dependent claims 6-9 recite second dose titration following second steady state serum value of testosterone, depending on the second steady state serum value of testosterone, less than about 400/F + b ng/dL, from about 400/F + b ng/dL to about 900/F + b ng/dL, or greater than about 900/F + b ng/dL.
Independent claim 54 recite similar limitation of first titration as independent claim 1 with specific/narrower range of steady state serum value of testosterone, less than about 460 ng/dL, from about 460 ng/dL to about 971 ng/dL, or greater than about 971 ng/dL and limitation to the subject (on anti-hypertensive therapy and/or diabetes... ).
Please note the steps as recited in 1b) to 1d) in claim 1, dependent claims 6-9, and 54b) to 54d) in independent claim 54, are construed as contingent limitations. As stated in MPEP 2111.04 II, The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent is (are) not met. If a first steady state serum value of testosterone in the subject is not established from about 3 hours to about 6 hours after administration of instantly claimed pharmaceutical composition, then following steps are not required to be performed.
According to FDA guidelines on testosterone (T) formulations (Testosterone Replacement Therapy Advisory Committee Briefing Document, September 17, 2014) as disclosed by instant specification (See page 1), an average T blood serum concentrations (Cavg) in the normal range of 300 to 1000 ng/dL in 75% of subjects, maximum T blood serum concentrations (Cmax) less than 1500 ng/dL in 85% of subjects, not more than 5% between 1800 and 2500 ng/dL, and none above 2500 ng/dL. The goal of testosterone replacement therapy (TRT) is to restore/maintain serum testosterone levels within physiologic range/ eugonadal (about 300-1100 ng/dL) and improve symptoms in hypogonadal men. A skilled artisan would have known to titrate the dose up or down for the desired range of serum value of testosterone accordingly. Dose titration/ adjustment is routine practice within the knowledge of a skilled artisan. Thus, instant claimed dose titration based on the steady state serum value of testosterone is considered as experimentation/optimization based on the general knowledge of testosterone replacement therapy (TRT).
Claim 33 b) to k) recites limitation “achieves a Cavg ...” “achieves a Cmax ...” “ reduces an average number of incorrect titrations or the risk of incorrect titrations...”, “decreases the risk of elevated blood pressure of the population of human subjects”, etc. Claim 38 depends on claim 33 and further recites limitation regarding systolic blood pressure. These limitation are construed as intended treatment results of the active method step of orally administering instantly claimed pharmaceutical composition comprising 400 mg of testosterone undecanoate (TU) , a non-sterol solubilizing agent, and a phytosterol or phytosterol ester, daily with a meal. These intended result do not materially limit instantly claimed method since such limitations do not result in manipulative difference in method steps of the claims. If the prior art teaches and suggests the same or similar method step as recited in claim 1, the method of the prior art would have achieved the intended results recited in instant claims and read on instant claimed methods. The burden of proof is shifted to the Applicant to show that the subject matter of the prior art does not possess the characteristic relied on whether the rejection is based on inherency under 35 U.S.C.102 or obviousness under 35 U.S.C. 103.
Claim 41 recites limitation regarding measuring the serum value of testosterone. Please note measurement of testosterone serum value is considered as routine experiment within the knowledge of POSA following clinical and laboratory standards that does not necessarily further contribute to the patentability of instant claimed method of treating testosterone deficiency.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-3, 5-11, 25, 29, 30, 33, 38, 40, 41, 46, and 54 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites i) “if the first Serum Value of testosterone is less than about 400/F + b ng/dL...”, ii) “the first Serum Value of testosterone is from about 400/F + b ng/dL to about 900/F + b ng/dL”...; iii) if the first Serum Value of testosterone is greater than about 900/F + b ng/dL.... The limitation “+ b ng/dL” is not a defined value and indefinite. An ordinary skilled in the art would not know what’s the range of serum value of testosterone. The metes and bounds of independent claim 1 is not clearly set forth for the protection desired.
Claim 2-3, 5-11, 25, 29, 30, 33, 38, 40, 41 and 46 are rejected due to dependency on claim 1.
Claim 7, 8, 9 also recite the limitation “400/F + b ng/dL” and “900/F + b ng/dL” that are indefinite.
Claim 3 recites a) a first dose is administered in the morning and a second dose is administered in the evening; and/or b) the first dose comprises about 200 mg TU, and the second dose comprises about 200 mg TU. The phrase “and/or” render claims 3 indefinite. It’s not clear if both limitation are required for administering 400mg of testosterone undecanoate. Claims 4 and 5 depend on claim 3 and are also rejected due to dependency on claim 3.
Claim 30 recites different subject: hypogonadal male and/or a population of human subjects. hypogonadal male is considered as human subjects. As such, the scope of claim 30 is not clear. Claims 33, 38, 40 , 46 and 54 also recite the phrase “and/or” which is indefinite. It’s not clear if all recited limitation are required or alternative limitations.
Claim 33 recites “the population comprises at least 10 subjects, at least 50 subjects, at least 100 subjects, at least 200 subjects, at least 500 subjects, or more” . A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation in the same claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In instant claim 33, “at least 10 subjects” is the broader limitation of population, “at least 50 subjects”, “at least 100 subjects”, “at least 200 subjects”, “at least 500 subjects” are the narrower limitation. It’s not clear what’s the limitation/scope of subjects. The lack of clarity renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
Claim 33 b) to k) recites limitation “achieves a Cavg ...” “achieves a Cmax ...” “ reduces an average number of incorrect titrations or the risk of incorrect titrations...” and/or “decreases the risk of elevated blood pressure of the population of human subjects”. Claim 38 depends on claim 33 and further recites limitation regarding blood pressure in the subject. These limitation are construed as intended results of the active method step of orally administering instantly claimed pharmaceutical composition comprising 400 mg of testosterone undecanoate (TU) , a non-sterol solubilizing agent, and a phytosterol or phytosterol ester, daily with a meal. As stated in MPEP 2173.05: “Notwithstanding the permissible instances, the use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear”. Claim 33 k) recites limitation “decreases the risk of elevated blood pressure of the population of human subjects”. It’s not clear how the extent of decreased risk of elevated blood pressure is measured/evaluated.
Claim 41 c) recites “a comparable method thereof”. It’s not clear what method is considered as comparable to 41 a) or b).
Claim 54 recites a subject on anti-hypertensive therapy and “exhibits an average change in systolic blood pressure of no more than 3.4 mmHg, an average change in diastolic blood pressure of no more than 1.8 mmHg, and/or an average change in heart rate of no more than 1.3 beats per minute”. It’s not clear if the change in blood pressure and/or heart rate is the result of anti-hypertensive therapy or intended result of administering instantly claimed TU composition.
Claim Rejections - 35 USC § 103
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 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 1-3, 5-11, 30, 41 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2020/0197412 A1, hereafter “Dudley’412, Applicant’s IDS dated 08/30/2023, Cite No. DQ*).
Dudley’412 discloses a method of treating conditions associated with a testosterone deficiency or absence of endogenous testosterone or chronic testosterone deficiency in a subject in need thereof with dose titration/adjustment. Dudley’412 teaches administering to the subject a defined dose (e.g. 198mg, 237mg twice daily ) of an oral pharmaceutical composition comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, followed by a series of steps, e.g. measuring the serum testosterone concentration in the subject and making a titration decision based on the measured serum testosterone concentration, e.g. increasing the dose of testosterone undecanoate administered when the measured serum testosterone concentration in the subject is less than about 425 ng/dL, decreasing each dose of testosterone undecanoate administered when the measured serum testosterone concentration in the subject is greater than about 970 ng/dL, and/or maintaining each dose of testosterone undecanoate administered when the measured serum testosterone concentration in the subject is between about 425 ng/dL and about 970 ng/dL (See [0010]-[0071], [0108]-[0149], [0233], claims 1-26).
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Dudley’412 teaches various initial dose and adjusted dose, e.g. 198mg, 237mg, 316mg or 398mg (BID) (See [0028], [0050], [0054], [0057], [0061], [0064], Table 1, claims 1 and 14) (which read on instant recited daily dose amount). For example, Dudley’412 teaches maintaining the dose of testosterone undecanoate (e.g. 198mg, administered twice daily) when the measured serum testosterone concentration in the subject is between about 425 ng/dL and about 970 ng/dL, or increasing the dose of testosterone undecanoate to 316 mg, administered twice daily, when the measured serum testosterone concentration in the subject is less than about 425 ng/dL, (See [0043], [0054], [0057], [0059], claim 1). Dudley’412 teaches the dose titration scheme outline in Table 1 (See [0169]), wherein the titration boundaries ( 425 to 970 ng/dL) fall within the eugonadal boundaries (300 to 1100 ng/dL) to achieve the desired testosterone Cavg within the eugonadal range (See [0233]).
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Regarding the meal limitation of step 1a), Dudley’412 teaches the oral pharmaceutical composition is administered in close proximity/immediately prior or after a meal, breakfast and/or dinner (See [0145], [0213]-[0214] ).
Regarding the timing limitation of step 1c), Dudley’412 teaches embodiments wherein the blood is drawn 4-8 hours (i.e., C4-8) after administrating of the oral pharmaceutical composition (See [0148], [0154], [0156] ), and/or the subject's testosterone concentration is measured after a first time period chosen from 1, 2, 3, 4, 5, 6, 7, and 8 hours (See [0150]) (which reads on instant recited 3-6 hours). Dudley’412 teaches the steady-state serum testosterone Cavg is estimated based on the measurement of testosterone in a single blood sample collected about 4 to 8 hours, or about 6 hours after oral testosterone dose(See [0154]). Dudley’412 explicitly teaches dose titration based on C6 (concentration 6 hours after morning dose) can effectively adjust a patient's oral TU dose to Cavg in the eugonadal range (See [0233], Table 3).
Regarding claims 2 and 3, Dudley’412 teaches the oral pharmaceutical composition is administered twice daily (BID) (See [0054], [0143], etc.), in the morning and in the evening (prior to dinner)(See [0213]-[0214], [0151]- [0152]). Dudley’412 also discloses the defined dose 198 mg administered twice daily (See [0054], [0166] )(which read on the first dose comprises about 200 mg TU, and the second dose comprises about 200 mg TU)
Regarding claim 5, Dudley’412 teaches various adjusted amount during the titration, e.g. increasing the dose of testosterone undecanoate to 316 mg, administered twice daily, when the measured serum testosterone concentration in the subject is less than about 425 ng/dL (See claim 1, Table 1) (which reads on instant claim 5i). Dudley’412 also teaches maintaining the dose of testosterone undecanoate (e.g. 198mg, 237mg administered twice daily) when the measured serum testosterone concentration in the subject is between about 425 ng/dL and about 970 ng/dL(See [0054], [0059], claim 1) (which reads on instant claim 5 ii).
Regarding second dose titration as recited in claim 6-11, Dudley’412 teaches repeating the steps of measuring the serum testosterone concentration followed by dose titration until the serum testosterone concentration in the subject is between 425 and 970 ng/dL (See [0120], [0140]). Dudley’412 teaches various adjusted dose amount, e.g. 158mg, 198mg, 237mg, 316mg or 398mg (BID) for titrating up or down (See Table 1, claims 1 and 14) that read on instant recited daily dose amount. For example, the dose of testosterone undecanoate is increased to 396 mg, administered twice daily, when the measured serum testosterone concentration in the subject is less than about 425 ng/dL(See [0165])(which read on instant claim 7a) and 10).
Regarding the testosterone undecanoate formulation as recited in claim 25 and 29, Dudley’412 teaches FDA approved JATENZO® comprising oleic acid, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), borage seed oil, peppermint oil, etc.(See [0008], [0205]). Dudley’412 further teaches variety of lipophilic and hydrophilic surfactant, e g. propylene glycol mono- and/or di-esters of fatty acids, Lauroglycol (propylene glycol monolaurate)(See [0100], alpha-tocopherol (See [0107]) and other component that can modulate testosterone ester absorption, e.g. phytosterol (See [0194]). Dudley’412 further teaches testosterone undecanoate formulation comprising various amount/ concentration of testosterone undecanoate, oleic acid, polyoxyl 40 hydrogenated castor oil(See [0205], [0211], Formulation A , Table 2; claim 3). For example, oral pharmaceutical composition comprises about 19.8 percent by weight of solubilized testosterone undecanoate, about 51.6 percent by weight of oleic acid, and about 16.1 percent by weight of polyoxyethylene (40) hydrogenated castor oil (See claim 3).
Regarding the subject limitation of claim 30 and 46, Dudley’412 teaches the subject is diagnosed with hypogonadal conditions (e.g. hypogonadal men), or conditions associated with structural/ genetic etiologies, testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy, etc. (See [0004], [0077]-0081], [0141], [0234]; claims 6-13).
Regarding claim 41, Dudley’412 teaches blood sample collected and measured in multiple plain,
EDTA and NaF-EDTA tubes. The plain tube will be incubated at RT to allow blood clotting for a minimum 30 mins, as recommended by Clinical and Laboratory Standards Institute (CLSI 2010). EDTA and NaF-EDTA tubes will be held on ice before centrifugation (See [0216] ). Dudley’412 also teaches a correction factor for T concentration in NaF-EDTA plasma, e.g. the NaF-EDTA plasma T concentration is
multiplied by 1.214 (See [0158]-[0159], [0226]-[0230]). Please note the measurement of testosterone serum value is considered as routine experiment following standard protocol within the knowledge of POSA that does not necessarily further contribute to the patentability of instant claimed method of treating testosterone deficiency.
Dudley’412 teaches normal range or "eugonadal range" is an average steady state plasma levels (concentrations) of testosterone of about 300-1100 ng/dL (See [0095]) and rationale of titration boundaries( 425 to 970 ng/dL) based on Cavg and C6 to achieve the eugonadal boundaries (See [0233])
Dudley’412 collectively teaches a method of treating testosterone deficiency in a subject in need thereof, comprising administering to the subject a defined dose (e.g. 198mg twice daily ) of an oral pharmaceutical composition comprising testosterone undecanoate, a non-sterol solubilizing agent (e.g. polyoxyl 40 hydrogenated castor oil/ Cremophor RH 40) and a phytosterol with dose titration/adjustment regimen based on the serum value of testosterone that could achieve the eugonadal range of testosterone (300 to 1100 ng/dL).
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instant claimed invention to further optimize the dosing regimen of testosterone undecanoate in testosterone therapy based on the collective teachings of Dudley’412 and general knowledge of testosterone therapy and arrive at instantly claimed invention with reasonable expectation of success. Dudley’412 teaches various dose adjustment based on the serum testosterone value with the titration boundaries ( 425 to 970 ng/dL) falling within the eugonadal boundaries (300 to 1100 ng/dL). A skilled artisan would be motivated to optimize the dose regimen of TU based on the serum value of testosterone to achieve the desired testosterone level with minimum risk of adverse events which is considered as routine practice of POSA in testosterone therapy. Where 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. MPEP 2144.05.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the collective teachings of prior art, together with exploration /optimization based on general knowledge of dose titration/adjustment in testosterone therapy. Therefore, instant invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1-3, 5-11, 25, 29, 30, 40, 41 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2020/0197412 A1, hereafter Dudley’412, Applicant’s IDS dated 08/30/2023, Cite No. DQ*) , further in view of Dhingra et al ( US20180021349A1, hereafter Dhingra’349, Applicant’s IDS dated 08/30/2023, Cite No. CZ*).
The collective teachings of Dudley’412 is elaborated in preceding 103 rejection and applied as before.
Dudley’412 is silent about the TU composition comprising TU and specific ratio of phytosterol esters as recited in claims 25 and 29.
Dhingra’349 teaches a self-emulsifying formulation SEDDS/SMEDDS/ SNEDDS for delivering therapeutic agent (e.g. testosterone undecanoate) with unique properties of spontaneity, homogeneity, dispersibility, fast release, and method of treating testosterone deficiency in a subject in need thereof with aforementioned TU formulation (See abstract, [0031], Examples 1-7; claims 1-22). Dhingra’349 teaches embodiments comprising TU and phytosterols (See Table 22) and in vivo dosing and pk profile of testosterone undecanoate in lipid formulations (See Example 5 and 14). Dhingra’349 teaches testosterone undecanoate formulation comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, at least one solubilizer, phytosterol fatty acid esters and/or dl-alpha-tocopherol, provides an average serum testosterone concentration at steady state falling in the range of about 300 to about 1140 ng/dL(See [0140])
Dhingra’349 teaches a pharmaceutical composition comprising (a)10-37.5 percent by weight of solubilized testosterone undecanoate; ( b ) 5 - 37.5 percent by weight of hydrogenated castor oil ethoxylate selected from the group consisting of Cremophor RH40, Kolliphor RH40 and Cremophor EL - 35 ; (c) 15-65 percent by weight of Maisine 35 -1, Oleic acid , Imwitor 742 , Capmul MCM , or Caproyl 90 , Lauroglycol 90 or Lauroglycol FCC; ( d ) 5-37.5 % phytosterol esters ; ( e ) 0 - 15 percent by weight of dl - alpha - tocopherol ; and ( f ) 0-15 percent castor oil , wherein the composition is self-dispersing when added to water and forms an emulsion , micro- emulsion , or nano- emulsion (See [0034], [0035], claims 1-22 ). Dhingra’349 explicitly teaches pharmaceutical composition comprising testosterone undecanoate, polyoxyl 40 hydrogenated castor oil, phytosterol esters at specific ratio (that read on instant claim 25 and 29): a ) about 18.2 % by weight of solubilized testosterone undecanoate; b ) about 15.0 % by weight of Cremophor RH40 ; c ) about 39.9 % by weight of Lauroglycol 90; d ) about 25.0 % by weight of one or more phytosterol esters ; and e ) about 2.0 % by weight of dl- alpha-tocopherol (See claim 18). Please note Lauroglycol™ 90 is propylene glycol monolaurate as taught by Dudley’412.
Dhingra’349 also teaches a method of treating testosterone deficiency in a subject in need thereof ( e.g. hypogonadal man), comprising administering the self- emulsifying TU oral formulation (See abstract, claims 19-21). Dhingra’349 teaches embodiments upon twice-daily oral administration, provides an average serum testosterone concentration at steady state falling in the range of about 300 to about 1140 ng/dL. The pharmaceutical composition provides a Cmax that, when administered with a meal, does not exceed 2500 ng/dL, preferably does not exceed 1800 ng/dL, and most preferably does not exceed 1500 ng/dL (See [0093] )
Regarding claim 40, Dhingra’349 teaches pharmacokinetic data with Cmax and Cave wherein the ratio of Cmax/ Cave for 0-24 hours is calculated to be less than 2.5 (See Example 13, Table 48)
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instant claimed invention to incorporate the self- emulsifying testosterone undecanoate composition taught by Dhingra’349 for the method of treating testosterone deficiency with dose titration/regimen taught by Dudley’412, together with further experimentation/optimization of TU dose based on the collective teachings of Dudley’412 and general knowledge of testosterone therapy and arrive at instantly claimed titration regimen with reasonable expectation of success. Dudley’412 teaches a dose titration regimen with titration boundaries ( 425 to 970 ng/dL) that could achieve the desired testosterone Cavg within the eugonadal range (300 to 1100 ng/dL). Dhingra’349 further teaches the advantage of self- emulsifying TU composition with unique properties, e.g. homogeneity, dispersibility, fast release, etc..
A skilled artisan would be motivated to combine the teachings of Dudley’412 and Dhingra’349 because both reference are directed to method of treating testosterone deficiency with oral TU composition and Dhingra’349 teaches the benefit of self-emulsifying oral TU formulation. One of ordinary skilled in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with exploration /optimization base on general knowledge of dose titration/adjustment in testosterone therapy. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1-3, 5-11, 25, 29, 30, 33, 38, 40, 41, 46, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2020/0197412 A1, hereafter Dudley’412, Applicant’s IDS dated 08/30/2023, Cite No. DQ*), in view of Dhingra et al ( US20180021349A1, Dhingra’349, Applicant’s IDS dated 08/30/2023, Cite No. CZ*) and NCT04467697 (Ambulatory Blood Pressure Monitoring (ABPM) Extension Study of Oral Testosterone Undecanoate in Hypogonadal Men, Ver. 2, 2021-01-13, retrieved from https://clinicaltrials.gov/study/NCT04467697)
The collective teachings of Dudley’412 and Dhingra’349 are elaborated in preceding 103 rejection and applied as before. Dudley’412 is silent about the subject limitation and intended treatment outcome/result as recited in claim 33, 38 and 54. Please note testosterone replacement therapy (TRT) is well-known treatment for testosterone deficiency and it’s common practice to explore different patient population under different conditions who might benefit from testosterone therapy with reduced adverse event .
NCT04467697 is six-month open-label study of SOV2012-F1 (TU) treatment extension of MRS-TU-2019 (NCT03198728). NCT04467697 disclosed the starting daily dose is 400 mg - (200 mg with morning meal and 200 mg with evening meal). Dosing is titrated up to a maximum of 800 mg SOV2012-F1 per day (400 mg in the morning and 400 mg in the evening) or titrated down to a minimum of 100 mg SOV2012-F1 per day (100 mg in the morning) based on plasma T wherein intermediate dose levels include total daily doses of 600 mg, 400 mg and 200 mg (See Arms and Interventions). NCT04467697 disclosed patient population including patients with treated/well-controlled conditions such as type 2 diabetes, hypertension (See Inclusion Criteria) and use Ambulatory Blood Pressure Monitoring ( ABPM ) monitoring 24-hour average systolic blood pressure for subjects (See Outcome Measures).
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instant claimed invention to explore/optimize TU dose regimen based on the combined teaching of prior art, together with general knowledge of dose titration/adjustment in testosterone therapy. A skilled artisan would be motivated to combine the teachings of prior art because all reference are directed to method of treating testosterone deficiency with oral TU composition, and would reasonably expect the optimization based on combined teachings of prior art would provide a safe, effective and convenient dosing regimen for more patients (including patients with hypertension) with minimum risk of adverse events in TRT. Dudley’412 is directed to teachings about JATENZO which is the first FDA-approved oral soft gel capsule for testosterone replacement therapy (TRT) in men with specific hypogonadal conditions, released in 2019 to treat testosterone deficiency without the liver toxicity issues. NCT04467697 teaches clinical trial with starting dose of 400mg and titration/dose adjustment for patient population with well-controlled conditions such as type 2 diabetes, hypertension. Where 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. MPEP 2144.05.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with exploration /optimization base on general knowledge of dose titration/adjustment in testosterone therapy. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1-3, 5-11, 25, 29, 30, 33, 38, 40, 41, 46, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2020/0197412 A1, Dudley’412, Applicant’s IDS dated 08/30/2023, Cite No. DQ*), in view of Dhingra et al ( US20180021349A1, Dhingra’349, Applicant’s IDS dated 08/30/2023, Cite No. CZ*), Giliyar et al. ( US 20120244215A1, hereafter Giliyar ‘215), and Swerdloff et al. (J Clin Endocrinol Metab. 2020 May 8;105(8): 2515-2531, doi: 10.1210/clinem/dgaa238, Applicant’s IDS dated 05/09/2025, A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men).
The collective teachings of Dudley’412 and Dhingra’349 are elaborated in preceding 103 rejection and applied as before.
Dudley’412 is silent about the ratio of Cmax to Cavg as recited in claim 40.
Giliyar ‘215 teaches a method for providing a serum testosterone concentration in a hypogonadal male within desired range (e.g. 300 to 1100 ng/dL, preferably between 400 to 600 ng/dL) with a ratio of serum testosterone Cmax to Cavg about 2.7 or less (See abstract, [0092], [0094], claims 1-42).
Giliyar ‘215 teaches titration regimen based on measurement of serum testosterone concentration according to clinical practice titration metrics (See Example 54, [0148]; claims 29-30 and 33) and effective dosing regimen for testosterone therapy in hypogonadal males (See Example 55, [0150]).
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Giliyar ‘215 also teaches steps of dose titration: orally administering to the male subject an initial regimen including a daily dose of a testosterone undecanoate-containing composition, wherein the testosterone undecanoate composition comprises about 14 wt % to about 35 wt % testosterone undecanoate and wherein the daily dose provides about 350 mg to about 650 mg of testosterone undecanoate to the male subject; 2) determining a dose titration metric based on measurement of serum testosterone concentration for the male subject on at least one titration node day within the initial regimen; and 3) orally administering to the male subject a maintenance regimen including a daily dose of testosterone undecanoate-containing composition, wherein the testosterone undecanoate-containing composition comprises about 14 wt % to about 35 wt % of the testosterone undecanoate-containing composition and wherein the maintenance regimen provides an daily dose of testosterone undecanoate to the subject based on the titration metric determined on the at least one titration node ay of the initial regimen sufficient to provide a serum testosterone plasma concentration within the target
range wherein the method provides a steady state ratio of serum testosterone Cmax to Cavg of 2.7 or less (See claims 29-42).
Regarding instant claim 33, Giliyar ‘215 teaches clinical study in human subjects (e.g. a group of at least 24 hypogonadal males) (See Example 48 and 49, [0136] [0138], claim 19, 37-40 ) that read on instantly claimed intended result, e.g. testosterone Cmax in the range of 300 ng/dL to 1100 ng/dL in 75% or more of hypogonadal males based on a minimum group size of 24 hypogonadal males, serum testosterone Cmax of 1500 ng/dL or less in less than or equal to 85% of hypogonadal males on a minimum group size of 24 hypogonadal males, etc.
Dudley’412 is silent about the subject limitation and intended treatment outcome/result as recited in claim 33, 38 and 54. Please note testosterone replacement therapy (TRT) is well-known treatment for testosterone deficiency and it’s common practice to explore different patient population who might benefit from testosterone therapy with reduced risk of adverse event.
Swerdloff summarizes phase III clinical trial of oral TU formulation (JATENZO®): CLAR-15012 (NCT00272278) in human subjects for short-term safety and efficacy (See whole article). Please note JATENZO (testosterone undecanoate) is the first FDA-approved oral softgel capsule for testosterone replacement therapy (TRT) in men with specific hypogonadal conditions, released in 2019 to treat testosterone deficiency without the liver toxicity issues. Swerdloff teaches effect of oral TU on hypertension wherein mean increases of systolic in BP patients with a history of hypertension who were receiving antihypertensive medication is about (5.5 ± 8.9 (SD) mm Hg) compared to those with no history of hypertension (4.3 ± 8.6 (SD) mm Hg)( See Table 7; page 13, left column).
Swerdloff teaches dose-titration study in hypogonadal men, wherein the starting dose for oral TU was 237 mg TU (150 mg of unesterified T equivalents), twice-daily (BID) which was administered immediately prior to a breakfast and dinner meal, approximately 12 hours apart... Based on the TCavg, oral TU doses could be up-titrated sequentially to 316 mg (200 mg T equivalents) and then 396 mg (250 mg T equivalents), or down-titrated to 198 mg (125 mg T equivalents) and then 158 mg (100 mg T equivalents) BID (See page 3, Study Design) (which also reads on titration regimen). Swerdloff further teaches oral TU dose titration pharmacokinetic and efficacy assessments with testosterone (T) Cavg values in the eugonadal range , and Cmax ≤1500 ng/d at least ≥85% of population, etc. (See Table 2-4)( which read on instant claim 33).
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instant claimed invention to explore/optimize TU dose regimen based on the combined teaching of prior art, together with general knowledge of dose titration/adjustment in testosterone therapy.
A skilled artisan would be motivated to combine the teachings of prior art because all reference are directed to method of treating testosterone deficiency with oral TU composition, and would reasonably expect the optimization based on combined teachings of prior art would provide a safe, effective and convenient dosing regimen with minimum risk of adverse events in TRT. Both Dudley’412 and Swerdloff are directed to teachings about JATENZO which is the first FDA-approved oral softgel capsule for testosterone replacement therapy (TRT) in men with specific hypogonadal conditions to treat testosterone deficiency without the liver toxicity issues. A skilled artisan would be motivated to develop/optimize dosing regimen of TU composition based on the teachings associated with JATENZO. Where 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. MPEP 2144.05.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with exploration /optimization base on general knowledge of dose titration/adjustment in testosterone therapy. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1-3, 5-11, 25, 29, 30, 33, 38, 40, 41, 46, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2020/0323880A1, hereafter Dudley’880, Applicant’s IDS dated 08/30/2023, Cite No. DT*), in view of Dhingra et al ( US20180021349A1, Dhingra’349, Applicant’s IDS dated 08/30/2023, Cite No. CZ*).
Dudley’880 teaches a method of treating conditions associated with a testosterone deficiency or absence of endogenous testosterone in a subject in need thereof (e.g. subject with existing hypertension who has adequately controlled blood pressure), comprising administering twice daily to the subject a defined dose (e.g. 237mg) of an oral pharmaceutical composition comprising testosterone undecanoate in a carrier comprising oleic acid and at least one hydrophilic surfactant (See abstract, [0148]-0149], Example 1 and 2, claims 1-26)
Regarding instant claims 1-3 and 5-11, Dudley’880 teaches dose titration/adjustment based on the serum testosterone concentration, e.g. collecting said subject's blood sample; measuring the serum testosterone concentration in the subject; if the measured serum testosterone concentration is less than about 425 ng/dL, increasing the dose of testosterone undecanoate administered; if the measured serum testosterone concentration is greater than about 970 ng/dL decreasing the dose of testosterone undecanoate; and if the measured serum testosterone concentration is between about 425 ng/dL and about 970 ng/dL, maintaining the dose of testosterone undecanoate administered (See [0075]-0079], Table 1, [0107], claim 22).
Dudley’880 teaches oral pharmaceutical composition is administered twice daily ( BID ) (See 0051]) and blood is drawn 4-8 hours ( i.e. C4-8 ), or 6 hour C6 after the administration of the dose (See [0098], [0100]). Dudley’880 teaches various initial dose and adjusted dose, e.g. 198mg, 237mg, 316mg or 398mg (BID) (See [0084], [0091]-[0092], Table 1,) (which read on instant recited daily dose amount). Dudley’880 teaches the dose of testosterone undecanoate is increased by about 40 mg to about 80 mg when the measured serum testosterone concentration in the subject is less than about 425 ng / dL, and/or decreased by about 10 mg to about 40 mg when the measured serum testosterone concentration in the subject is greater than about 970 ng / dL (See claims 24 and 25)
Dudley’880 teaches the dose titration scheme outline in Table 1 (See [0096]), wherein the titration boundaries ( 425 to 970 ng/dL) fall within the eugonadal boundaries.
Regarding the TU composition, Dudley’880 teaches pharmaceutical composition comprises a testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a total lipophilic surfactant to total hydrophilic surfactant ratio (w w ) falling
in the range of about 6:1 to 3.5 :1 , upon once- or twice - daily oral administration, provides an aver
age serum testosterone concentration at steady state falling in the range of about 425 to about 970 ng / dL(See [0107]). , Dudley’880 teaches variety of hydrophilic surfactant, e. g. hydrogenated castor oil ethoxylates Cremophor RH 40 (See [0113] ) and lipophilic surfactant, e.g. , Lauro glycol ( propylene glycol monolaurate) (See [0115]-[0121]) and other components that can modulate testosterone
ester absorption, e.g. phytosterols (See [0141]).
Regarding claim 41, Dudley’880 teaches measuring the subject's serum testosterone concentration and dividing that concentration by a conversion factor, e.g. 1.214 to yield the expected T concentration in NaF-EDTA plasma(See [0103]).
Regarding instant claim 33, 38 and 54, Dudley’880 teaches clinical trial of JATENZO in 166 adult hypogonadal males ( NCT02722278) wherein the subject has a history of hypertension and being treated with antihypertensive therapy (See [0068], [0070], Experiment 1 and 2, [0142]-0146], [0147]) . Dudley’880 teaches embodiments wherein administration of the oral pharmaceutical composition results an average increase of systolic blood pressure of 4.9 mm Hg or 2.8 mm Hg (See [0061], claims 15,16). Dudley’880 also teaches percentage of patients who received JATENZO had Cmax less than or equal to 1500 ng / dL , between 1800 and 2500 ng / dL , and greater than 2500 ng / dL at the final PK visit were 83%, 3 %,and 3 %, respectively (See [0152])(which reads on instant claim 33).
Dudley’880 is silent about the TU composition comprising TU and specific ratio of phytosterol esters as recited in claims 25 and 29.
The collective teaching of Dhingra’349 is elaborated in preceding 103 rejections and applied as before. Dhingra’349 teaches a method of treating testosterone deficiency in a subject in need thereof ( e.g. hypogonadal man), comprising administering self- emulsifying TU oral formulation and explicitly teaches pharmaceutical composition comprising testosterone undecanoate, polyoxyl 40 hydrogenated castor oil, phytosterol esters at specific ratio (that read on instant claim 25 and 29): a ) about 18.2 % by weight of solubilized testosterone undecanoate; b ) about 15.0 % by weight of Cremophor RH40 ; c ) about 39.9 % by weight of Lauroglycol 90; d ) about 25.0 % by weight of one or more phytosterol esters ; and e ) about 2.0 % by weight of dl- alpha-tocopherol.
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instant claimed invention to incorporate the self- emulsifying testosterone undecanoate composition taught by Dhingra’349 for the method of treating testosterone deficiency with dose titration/regimen in different subject population taught by Dudley’880, together with further experimentation/optimization of TU dose based on the collective teachings of Dudley’880 and general knowledge of testosterone therapy and arrive at instantly claimed method of treating testosterone deficiency with reasonable expectation of success. Dudley’880 teaches a dose titration regimen with titration boundaries ( 425 to 970 ng/dL) that could achieve the desired testosterone Cavg within the eugonadal range. Dudley’880 also teaches variety of subject population including subject on anti-hypertension therapy. Dhingra’349 further teaches the advantage of self- emulsifying TU composition with unique properties, e.g. homogeneity, dispersibility, fast release, etc..
A skilled artisan would be motivated to combine the teachings of Dudley’880 and Dhingra’349 because both reference are directed to method of treating testosterone deficiency with oral TU composition and Dhingra’349 teaches the benefit of self-emulsifying oral TU formulation. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with exploration /optimization base on general knowledge of dose titration/adjustment in testosterone therapy. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting Rejection
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 1-3, 5-11, 25, 29, 30, 33, 38, 40, 41, 46 and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12403146 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because reference claims anticipate or render instant claims prima facie obvious.
Reference claims are directed to a method of treating testosterone deficiency in a subject in need thereof, comprising similar steps as instant claims:
a) performing a treatment regimen comprising orally administering to the subject 400 mg of testosterone undecanoate (TU) daily with a meal, wherein the TU is administered in a pharmaceutical composition comprising TU, a non-sterol solubilizing agent effective for solubilization of the TU, and a phytosterol or phytosterol ester;
b) establishing a first steady state serum concentration of testosterone;
c) following step (b), providing a first steady state Serum Value of testosterone in the subject that is measured from about 3 hours to about 6 hours after administration of the pharmaceutical composition; and
d) performing a first titration of the testosterone undecanoate, wherein:
i) if the first Serum Value of testosterone is less than about 460 ng/dl, then orally administering to the subject about 600 mg TU daily to establish a second steady state Serum Value of testosterone that is higher than the first steady state Serum Value of testosterone;
ii) if the first Serum Value of testosterone is from about 460 ng/dl to about 971 ng/dl, then continuing to orally administer to the subject about 400 mg TU daily to maintain the first steady state Serum Value of testosterone; or
iii) if the first Serum Value of testosterone is greater than about 971 ng/dl, then orally administering to the subject about 200 mg TU daily to establish a second steady state Serum Value of testosterone that is lower than the first steady state Serum Value of testosterone.
Reference claim 1 is essentially the same as instant claim 1 with narrower/defined steady state serum value of testosterone at 460 ng/dl and 971 ng/dl ( which also reads on instant claim 54).
Reference claims 2, 3, 4 reciting administering the pharmaceutical composition twice daily, with limitation of first dose and second dose that read on instant claim 2, 3 and 5 respectively.
Reference claims 6- 8 recite orally administering TU daily to the subject to establish a third steady state serum value of testosterone (which read on instant claims 7-9).
Reference claims 13-14 reciting limitations of pharmaceutical composition a) about 18.2% by weight of solubilized testosterone undecanoate; b) about 15.0% by weight of polyoxyl 40 hydrogenated castor oil; c) about 39.9% by weight of propylene glycol monolaurate; d) about 25.0% by weight of one or more phytosterol esters; and e) about 2.0% by weight of di-alpha-tocopherol and/or an ester or acetate thereof (which read on instant claims 25 and 29).
Reference claim 15 and 16 reciting subject/population a) the subject is a hypogonadal male; b) the subject has not previously been administered TU or other testosterone replacement therapy for a period of at least seven days or a period of time sufficient to completely wash exogenous testosterone from the subject; and/or c) the method is performed on a population of human subjects (that read on instant claim 30, 33 and 46).
Reference claim 17 reciting limitation of systolic blood pressure (which read on instant claim 38 and 54).
Reference claim 18-21 reciting limitation of measuring serum value of testosterone, e.g. measuring of serum clotted at room temperature for about 30 minutes prior to centrifugation in a tube (which read on instant claim 41).
Reference claims recite essentially the same or similar limitation as instant claims with narrower/defined steady state serum value of testosterone at 460 ng/dl and 971 ng/dl, thus anticipate or at least render instant claims prima facie obvious.
The instant application shares one common inventor/applicant/assignee with the reference patent. Instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Claims 1-3, 5-11, 30, 33, 38, 41, 46 and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12295961 B2, in view of Dudley et al. (US 2020/0323880A1, Dudley’880, Applicant’s IDS dated 08/30/2023, Cite No. DT*).
Reference claims are directed to a method of treating male hypogonadism in a subject in need thereof, the method comprising administering to the subject the oral formulation comprising: a) testosterone undecanoate; b) from about 10% to about 90% by weight of a non-sterol solubilizing agent effective for solubilization of the testosterone undecanoate; and c) from about 2% to about 45% by weight of a mixture of phytosterol esters, wherein the mixture of phytosterol esters comprises esters of beta-sitosterol and stigmasterol.
Reference claims are silent of dosing titration as recited in instant claims.
The collective teaching of Dudley’880 is elaborate in preceding 103 rejection and applied as before. Dudley’880 teaches a dose titration regimen with titration boundaries ( 425 to 970 ng/dL) that could achieve the desired testosterone Cavg within the eugonadal range. Dudley’880 also teaches variety of subject population including subject on anti-hypertension therapy.
It would have been prima facie obvious to one of ordinary skilled in the art to incorporate the self- emulsifying testosterone undecanoate composition taught by reference claims for the method of treating testosterone deficiency with dose titration/regimen in different subject population taught by Dudley’880, together with further experimentation/optimization of TU dose based on the collective teachings of Dudley’880 and general knowledge of testosterone therapy. A skilled artisan would be motivated to combine reference claims with Dudley’880 in searching for an effective and safe dosing regimen that could achieve the desired testosterone concentration in testosterone therapy.
The instant application shares one common inventor/applicant/assignee with the reference patent. Instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Claims 1-3, 5-11, 30, 33, 38, 41, 46 and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10576089 B2, in view of Dudley et al. (US 2020/0323880A1, Dudley’880, Applicant’s IDS dated 08/30/2023, Cite No. DT*).
Reference claims are directed to a method of treating male hypogonadism in a subject in need thereof, comprising administering to the subject an oral formulation comprising: a) testosterone undecanoate; b) from about 10% to about 90% by weight of a non-sterol solubilizing agent effective for solubilization of the testosterone undecanoate; and c) from about 2% to about 45% by weight of a mixture of phytosterols or phytosterol esters, wherein the mixture comprises from 40% to 58% by weight of beta-sitosterol or esters thereof; from 20% to 30% by weight of campesterol or esters thereof; from 14% to 22% by weight stigmasterol or esters thereof; from 0 to 6% by weight brassicasterol or esters thereof; from 0 to 5% by weight sitostanol or esters thereof; and from 0 mg/g to 15 mg/g tocopherols; wherein the phytosterols or phytosterol esters provide increased plasma levels of testosterone following oral administration in comparison to the plasma levels of testosterone produced following oral administration of testosterone undecanoate in a formulation free of phytosterols and phytosterol esters.
Reference claims 6-8 recite non-sterol solubilizing agent, e.g. propylene glycol monolaurate, polyoxyl 40 hydrogenated castor oil.
Reference claims are silent of dosing titration as recited in instant claims.
The collective teaching of Dudley’880 is elaborate in preceding 103 rejection and applied as before. Dudley’880 teaches a dose titration regimen with titration boundaries ( 425 to 970 ng/dL) that could achieve the desired testosterone Cavg within the eugonadal range. Dudley’880 also teaches variety of subject population including subject on anti-hypertension therapy.
It would have been prima facie obvious to one of ordinary skilled in the art to incorporate the self- emulsifying testosterone undecanoate composition taught by reference claims for the method of treating testosterone deficiency with dose titration/regimen in different subject population taught by Dudley’880, together with further experimentation/optimization of TU dose based on the collective teachings of Dudley’880 and general knowledge of testosterone therapy and arrive at instantly claimed method of treating testosterone deficiency with reasonable expectation of success. A skilled artisan would be motivated to combine reference claims with Dudley’880 in searching for an effective and safe dosing regimen that could achieve the desired testosterone concentration with minimum risk of adverse event in testosterone therapy.
The instant application shares one common inventor/applicant/assignee with the reference patent. Instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
NCT03198728, Efficacy and Safety of Oral Testosterone Undecanoate in Hypogonadal V24 06/30/ 2020, retrieved from https://clinicaltrials.gov/study/NCT03198728.
JatenzoTM Briefing Document 2018, ("Oral Testosterone Undecanoate Capsules (JatenzoTM) for Testosterone Replacement Therapy in Hypogonadal Men" by Clarus Therapeutics, Inc., January 9, 2018, Applicant’s IDS dated 08/30/2023, NPL Cite No. EB). JatenzoTM Briefing Document 2018 teaches effect of JatenzoTM in patient with hypertension wherein the limitation of blood pressure are similar as recited in instant claim 38 and 54(See Table 10).
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JATENZO (testosterone undecanoate) label 2019. JATENZO 2019 label teaches dose titration based on measured serum testosterone concentrations 6 hours after the morning dose in plain tubes, clotted at room temperature for 30 minutes prior to centrifugation, with titration boundary 425 ng/dL- 970 ng/dL (See 2.2. Dosing and Dose Adjustment Information; 12. 3 Pharmacokinetics).
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JATENZO 2019 also teaches clinical trial wherein blood pressure/ 24-hour ABPM was monitored, and the mean change in 24-hour systolic BP and diastolic BP from baseline to final on-treatment visit was 4.9 mmHg (95% CI 3.5, 6.4) and 2.5 mmHg (95% CI 1.5, 3.6), respectively(See 6. 1. Clinical trial experience).
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/LIYUAN MOU/ Examiner, Art Unit 1628
/JARED BARSKY/ Primary Examiner, Art Unit 1628