DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Interpretation
The claim term trans-3-hexenoyl-GHRH(1-44)-NH2 is shown in Figure 1 and is also known in the art as tesamorelin, TH9507, and EGRIFTA™, EGRIFTA SV™ and EGRIFTA WR™.
BRI of “bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 at a concentration of 1 mg/mL” is defined according to para. [0067] of the original specification: “as used herein means that one or more pharmacokinetic (PK) parameters following administration of the GHRH molecule to subjects do not significantly differ between the two treatment regimens, as determined using a suitable statistical standard.” The statistical standard is exemplified in the bioequivalence studies presented in Examples 1 and 2 of the original specification. In addition, the term is known to one of ordinary skill in the art as evidenced by FDA guidance on bioequivalence (www.fda.gov/media/70115/download).
Claim Rejections - 35 USC § 112 - withdrawn
The rejections of claims 19-24, 32, and 52-54 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement and with the enablement requirement are withdrawn in view of the arguments filed May 21, 2026.
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 pre-AIA 35 U.S.C. 103(a) 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 19-24, 32, and 52-54 are rejected under 35 U.S.C. 103 as being unpatentable over Shingel et al. (US 2014/0249083 A1; pre-grant publication of US 8,871,713 B2).
Shingel et al. teach stabilized formulations of trans-3-hexenoyl-GHRH(1-44)-NH2 for pharmaceutical use (para. [0009], [0052], Example 1, Example 5). The teachings of this reference map to claim 19 as follows:
Claim 19
Shingel et al.
A method of administering trans-3-hexenoyl-GHRH(1-44)-NH2 or a pharmaceutically acceptable salt thereof to a subject
Shingel et al. teach trans-3-hexenoyl-GHRH(1-44)-NH2 for use in the treatment of at least one of HIV-associated lipodystrophy, HIV-lipohypertrophy, abdominal obesity, GH deficiency, frailty, mild cognitive impairment, immune deficiency, wasting associated with a chronic disease or long-term disease, or malnutrition associated with a chronic disease or long-term disease (para. [0052], Example 1). Using trans-3-hexenoyl-GHRH(1-44)-NH2 for treatment requires administering it to a subject, thereby satisfying the claim preamble.
to obtain plasmatic levels of trans-3-hexenoyl-GHRH(1-44)-NH2 bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 at a concentration of 1 mg/mL
Shingel et al. is silent regarding the claimed function of bioequivalence.
by administering to the subject
Shingel et al. teach a method for inducing growth hormone secretion in a subject in need thereof, said method comprising administering to said subject an effective amount of the pharmaceutical formulation (para. [0049]). Shingel et al. teach subcutaneous administration (para. [0054]). Therefore, Shingel et al. satisfy the limitation of administering to a subject.
about 1.23 to about 1.32 mg of trans-3-hexenoyl-GHRH(1-44)-NH2
Shingel et al. teach trans-3-hexenoyl-GHRH(1-44)-NH2 can be administered at a daily dose of about 0.1 mg to about 20 mg (para. [0053]). Shingel et al. teach administration of the active principal ingredient (e.g. trans-3-hexenoyl-GHRH(1-44)-NH2) at a dose greater than or equal to about 1 mg, greater than or equal to about 2 mg, from about 1 mg to about 4 mg, from about 2 mg to about 4 mg, or about 1, 2, 3 or 4 mg (para. [0159]). Therefore, Shingel et al. teach a range of doses that includes the claimed range of doses.
at a concentration of 7.5 mg/ml or more.
Shingel et al. teach stabile formulations comprising 8 mg/mL tesamorelin in a carrier of 10% HP-b-CD, 3.5% or 5% of mannitol, and 10 mM of sodium lactate at pH 6 (Example 5, Tables 4-5, Figure 16, para. [0249]-[0250]).
Therefore, the prior art teaches a concentration, 8 mg/ml, that falls within the claimed range 7.5 mg/ml or more.
Shingel et al. teach a range of doses that include the claimed range of about 1.23 to about 1.32 mg but does not teach an embodiment that falls within the claimed range nor do Shingel et al. explicitly teach the claimed range. Shingel et al. are silent with respect to bioequivalence. See claim map above.
It would have been obvious to use the formulations comprising 8 mg/mL trans-3-hexenoyl-GHRH(1-44)-NH2 in a carrier of 10% HP-b-CD, 3.5% or 5% of mannitol, and 10 mM of sodium lactate at pH 6 taught by Shingel et al. (Example 5, Tables 4-5, Figure 16, para. [0249]-[0250]) in method of administering trans-3-hexenoyl-GHRH(1-44)-NH2 to a subject in need thereof (para. [0052]). One of ordinary skill in the art would have been motivated to do so given that Shingel et al. teach that this composition has the benefit of long term chemical stability and is suitable for pharmaceutical use (Example 5, Tables 4-5, Figure 16, para. [0249]-[0250]).
Regarding the range of doses, MPEP § 2144.05(I) states: In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
In the instant case, the claimed range about 1.23 to about 1.32 mg lies inside the prior art ranges 0.1 mg to about 20 mg (para. [0053]), greater than or equal to about 1 mg, from about 1 mg to about 4 mg, from about 2 mg to about 4 mg, and about 1, 2, 3 or 4 mg (para. [0159]). Therefore, the claimed range is prima facie obvious over the prior art.
In addition, MPEP § 2144.05(II)(A) states: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
In the instant case, it would have been routine optimization to arrive at the claimed invention because the claimed parameter dose is recognized as a result-effective variable, i.e., a variable which achieves a recognized result. The dose achieves the result of inducing growth hormone secretion in a subject in need thereof (Shingel et al., para. [0049]), which in turn can have the effective of treating HIV-associated lipodystrophy, HIV-lipohypertrophy, abdominal obesity, GH deficiency, frailty, mild cognitive impairment, immune deficiency, wasting associated with a chronic disease or long-term disease, or malnutrition associated with a chronic disease or long-term disease (Shingel et al., para. [0052]).
There would have been a reasonable expectation of success to arrive at the claimed dose because the prior art ranges 0.1 mg to about 20 mg (para. [0053]), greater than or equal to about 1 mg, from about 1 mg to about 4 mg, from about 2 mg to about 4 mg, and about 1, 2, 3 or 4 mg (para. [0159]), which encompasses the claimed range 1.23 to 1.32 mg, constitutes a finite number of identified, predictable solutions to the problem of finding the effective dose of trans-3-hexenoyl-GHRH(1-44)-NH2.
There is no evidence on record that the claimed range 1.23 to 1.32 mg is critical for the prior art purpose of inducing growth hormone secretion and treating HIV lipodystrophy in a subject in need thereof. One of ordinary skill in the art would expect all of the prior art ranges to be therapeutically useful based on the teaching of Shingel et al.
Regarding the limitation “to obtain plasmatic levels of trans-3-hexenoyl-GHRH(1-44)-NH2 bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 at a concentration of 1 mg/mL”, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The cited art renders a method of administering the same formulation, at the same dose, in the same manner, to the same patients as the instant claims. The claimed effect of bioequivalence flows from this obvious method. In addition, the expected benefit of the entire range taught by Shingel et al. being effective for treatment outweighs the benefit of bioequivalence reported in the specification.
Therefore, claim 19 is obvious over Shingel et al.
Regarding claims 20 and 54, the claimed range “about 1.28 mg” inside the prior art ranges 0.1 mg to about 20 mg (para. [0053]), greater than or equal to about 1 mg, from about 1 mg to about 4 mg, from about 2 mg to about 4 mg, or about 1, 2, 3 or 4 mg (para. [0159]). Therefore, the claimed range is prima facie obvious over the prior art.
Regarding claim 21, Shingel et al. teach the concentration 8 mg/ml, which falls within the claimed range of concentration of about 7.5 to about 8.5 mg/mL.
Regarding claim 22, Shingel et al. teach the acetate salt (para. [0227]).
Regarding claim 23, Shingel et al. teach subcutaneous injection (para. [0054]).
Regarding claim 24, Shingel et al. teach resuspending lyophilized trans-3-hexenoyl-GHRH(1-44)-NH2 in a suitable amount of a pharmaceutically acceptable diluent to obtain a trans-3-hexenoyl-GHRH(1-44)-NH2 solution at a concentration of 8 mg/mL (para. [0065], [0152], [0153], [0190], [0198]; Example 5). Shingel et al. teach administration of the resuspended trans-3-hexenoyl-GHRH(1-44)-NH2 solution in a volume needed to deliver the desired dose (para. [0159]).
Regarding claim 32, Shingel et al. teach that the subject suffers from HIV-associated lipodystrophy (para. [0052]).
Regarding claim 52, Shingel et al. teach the concentration 8 mg/ml, which falls within the claimed range of concentration of about 7.8 to about 8.2 mg/ml.
Regarding claim 53, Shingel et al. teach the concentration of 8 mg/ml.
Response to Arguments
Applicant's arguments filed May 21, 2026, have been fully considered but they are not persuasive.
Applicant argues that the “present application discovered the unexpected results of a non-linear pharmacokinetic relationship between the claimed concentration of about 7.5 mg/ml or more trans-3-hexenoyl-GHRH(1-44)NH2 in a dose of about 1.23 to about 1.32 mg”. Reply, pages 4-5, bridging para. Applicant goes on to argue that linear pharmacokinetics where equal doses produce equal plasma levels regardless of formulation concentration are expected by POSITA. Reply, page 5, first para. This argument is not persuasive because arguments of counsel cannot take the place of evidence (MPEP § 716.01(c)(II)). The specification provides evidence of a non-linear pharmacokinetic relationship between the claimed concentration of about 7.5 mg/ml or more trans-3-hexenoyl-GHRH(1-44)NH2 in a dose of about 1.23 to about 1.32 mg. However, the specification does not provide evidence that the non-linear relationship is unexpected in view of the art. This point is critical for establishing that the results in the specification are unexpected, not expected in view of the prior art (MPEP §§ 716.02(b)(I), 716.02(c)(II)).
This argument is also not persuasive because even if the results are unexpected with respect to bioequivalence, this is insufficient to outweigh the evidence of expected results with respect to treatment (MPEP § 716.02(c)(I)). POSITA would expect the claimed dose to achieve the result of inducing growth hormone secretion in a subject in need thereof (Shingel et al., para. [0049]), which in turn can have the effective of treating HIV-associated lipodystrophy, HIV-lipohypertrophy, abdominal obesity, GH deficiency, frailty, mild cognitive impairment, immune deficiency, wasting associated with a chronic disease or long-term disease, or malnutrition associated with a chronic disease or long-term disease (Shingel et al., para. [0052]) because the claimed dose 1.23 to 1.32 mg falls within the range of doses taught to be useful for these purposes, 0.1 mg to about 20 mg (para. [0053]), greater than or equal to about 1 mg, from about 1 mg to about 4 mg, from about 2 mg to about 4 mg, and about 1, 2, 3 or 4 mg (para. [0159]). This evidence of an expected result outweighs the benefit of bioequivalence.
Next, Applicant traverses the rejection on the grounds that the evidence in the specification demonstrates a narrow criticality window for bioequivalence. Reply page 5, second para. This is not persuasive because there is no evidence on record that the claimed range 1.23 to 1.32 mg is critical for the prior art purpose of inducing growth hormone secretion and treating HIV lipodystrophy in a subject in need thereof. One of ordinary skill in the art would expect all of the prior art ranges to be therapeutically useful based on the teaching of Shingel et al.
Next Applicant traverses the rejection on the grounds that Shingel does not teach the concept of bioequivalence. Reply, page 5, third para. This is not persuasive because as stated above the claimed range is not critical for the prior art use of therapeutic effectiveness. Any benefit with respect to bioequivalence flows from using this obvious dose.
Finally, Applicant traverses the rejection on the grounds that the routine optimization rationale is invalid because bioequivalence is not a recognized result that dose optimization would achieve. Reply, pages 5-6, bridging para. This argument is not persuasive because the routine optimization rationale is based on optimizing an effective dose, which is a result effective variable recognized in the art.
For these reasons, the rejection is maintained.
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 CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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