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
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19-24, 32, and 52-54 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
According to para. [0005] of the specification, tesamorelin was first approved for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy at a dose of 2 mg administered by subcutaneous injection of 2 ml of a 1 mg/mL tesamorelin solution into abdominal skin. The dose was supplied in two vials each comprising 1 mg of lyophilized tesamorelin. To use, patients were required to resuspend the lyophilized tesamorelin in the first vial with 2.2 mL of sterile water using a syringe with a first mixing needle, collect the prepared tesamorelin solution from the first vial, change the needle, add the prepared tesamorelin solution to the second vial with the second mixing needle, collect the prepared tesamorelin solution from the second vial, replace the second mixing needle with an injection needle, and subcutaneously inject 2 mL of the prepared tesamorelin solution. The instant application is an attempt to provide a simpler and more convenient formulation wherein a small dose of a more concentrated solution is administered.
Claim 19 is drawn to a method of administering trans-3-hexenoyl-GHRH(1-44)-NH2 (tesamorelin) or salt thereof to obtain plasmatic levels that are bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 at a concentration of 1 mg/mL, comprising administering a subject about 1.23 to about 1.32 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 or salt thereof at a concentration of about 7.5 mg/ml or more.
Therefore, to satisfy the written description requirement, the specification must support possession of a formulation with the following function and structure:
Function
bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 at a concentration of 1 mg/mL
Structure
a dose of trans-3-hexenoyl-GHRH(1-44)-NH2 or salt thereof that is
about 1.23 to about 1.32 mg
at a concentration of about 7.5 mg/ml or more
There is significant unpredictability pertaining to bioequivalence as evidenced by the Examples in the specification. In the instant specification, determination of bioequivalence could not be predicted but instead required empirical testing and measurement. Example 1 of the specification presents a bioequivalence study in humans with 1.2 mg, 1.36, and 1.6 mg of an 8 mg/ml tesamorelin formulation. Neither administration of 1.2 mg, 1.36, nor 1.6 mg of the 8 mg/ml formulation were bioequivalent to administration of 2 mg of tesamorelin. Based on this result, the study concluded that a dose above 1.2 mg and below 1.36 mg of the 8 mg/ml formulation would be suitable to obtain bioequivalence. Example 2 corroborated this conclusion by testing a 1.28 mg of a 8 mg/ml formulation which was found to be bioequivalent.
Compared to the scope of the claim, the reduction to practice in the specification is narrow.
Claimed Scope
Reduction to Practice
trans-3-hexenoyl-GHRH(1-44)-NH2 or salt thereof
A single structure tesamorelin was tested versus a range of salts.
about 1.23 to about 1.32 mg
A single dose, 1.28 mg was tested in Example 2.
at a concentration of about 7.5 mg/ml or more
Only a single concentration, 8 mg/ml was tested.
Carrier is unspecified
Only a single carrier was tested: 10% hydroxypropyl- b -cyclodextrin and 3% Mannitol, pH 5.9-6.
Given the breadth of the claims and the unpredictability shown in Example 1 of the specification, one of ordinary skill in the art would not consider the actual reduction to practice to be representative of the full scope of the claims.
The specification fails to provide guidance in the form of structure-function studies or description of the chemical and physical properties of the full genus. It is not clear from the specification how the claimed function of bioequivalence would be impacted by: 1) a salt of trans-3-hexenoyl-GHRH(1-44)-NH2 ; 2) doses other than 1.28 mg, 3) concentrations other than 8 mg/ml; and 4) carriers other than 10% hydroxypropyl- b -cyclodextrin and 3% Mannitol, pH 5.9-6. Considering the unpredictability illustrated in Example 1, the burden is on Applicant to provide guidance in the specification that is commensurate in scope with the claims.
Therefore, the specification fails to support a conclusion that Applicant was in possession of the full scope of the claims at the time the application was filed.
Claims 19-24, 32, and 52-54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for obtaining 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 by administering 1.28 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 at a concentration of 8 mg/ml in 10% hydroxypropyl-p-cyclodextrin and 3% Mannitol, pH 5.9-6, it is not enabled for obtaining the same with salts of trans-3-hexenoyl-GHRH(1-44)-NH2, other concentrations, and other carriers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Nature of the Invention and State of the Prior Art
According to para. [0005] of the specification, tesamorelin was first approved for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy at a dose of 2 mg administered by subcutaneous injection of 2 ml of a 1 mg/mL tesamorelin solution into abdominal skin. The dose was supplied in two vials each comprising 1 mg of lyophilized tesamorelin. To use, patients were required to resuspend the lyophilized tesamorelin in the first vial with 2.2 mL of sterile water using a syringe with a first mixing needle, collect the prepared tesamorelin solution from the first vial, change the needle, add the prepared tesamorelin solution to the second vial with the second mixing needle, collect the prepared tesamorelin solution from the second vial, replace the second mixing needle with an injection needle, and subcutaneously inject 2 mL of the prepared tesamorelin solution. The instant application is an attempt to provide a simpler and more convenient formulation.
Breadth of the Claims
Claim 19 is drawn to a method of administering trans-3-hexenoyl-GHRH(1-44)-NH2 (tesamorelin) or salt thereof to obtain plasmatic levels that are bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 at a concentration of 1 mg/mL, comprising administering a subject about 1.23 to about 1.32 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 or salt thereof at a concentration of about 7.5 mg/ml or more.
The scope of the claim includes administering a formulation with the following function and structure:
Function
bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH(1-44)-NH2 at a concentration of 1 mg/mL
Structure
a dose of trans-3-hexenoyl-GHRH(1-44)-NH2 or salt thereof that is
about 1.23 to about 1.32 mg
at a concentration of about 7.5 mg/ml or more
Level of Predictability
There is significant unpredictability pertaining to bioequivalence. In the instant specification, determination of bioequivalence required empirical testing and measurement. Example 1 of the specification presents a bioequivalence study in humans with 1.2 mg, 1.36, and 1.6 mg of an 8 mg/ml tesamorelin formulation. Neither administration of 1.2 mg, 1.36, nor 1.6 mg of the 8 mg/ml formulation were bioequivalent to administration of 2 mg of tesamorelin. The study concluded that a dose above 1.2 mg and below 1.36 mg of the 8 mg/ml formulation would be suitable to obtain bioequivalence. Example 2 confirmed this result by testing a 1.28 mg of a 8 mg/ml formulation which was found to be bioequivalent.
Actual Reduction to Practice
Compared to the scope of the claim, the reduction to practice in the specification is narrow.
Claimed Scope
Reduction to Practice
trans-3-hexenoyl-GHRH(1-44)-NH2 or salt thereof
Single structure tesamorelin was tested.
about 1.23 to about 1.32 mg
A single dose, 1.28 mg was tested in Example 2.
at a concentration of about 7.5 mg/ml or more
Only a single concentration, 8 mg/ml was tested.
Carrier is unspecified
Only a single carrier was tested: 10% hydroxypropyl- b -cyclodextrin and 3% Mannitol, pH 5.9-6.
Level of Guidance in the Specification
The specification fails to provide guidance in the form of structure-function studies or description of the chemical and physical properties of the full genus. It is not clear from the specification how the claimed function of bioequivalence would be impacted by: 1) a salt of trans-3-hexenoyl-GHRH(1-44)-NH2 ; 2) doses other than 1.28 mg, 3) concentrations other than 8 mg/ml; and 4) carriers other than 10% hydroxypropyl- b -cyclodextrin and 3% Mannitol, pH 5.9-6. Considering the unpredictability illustrated in Example 1, the burden is on Applicant to provide guidance in the specification that is commensurate in scope with the claims.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if any salts of trans-3-hexenoyl-GHRH(1-44)-NH2, doses other than 1.28 mg, concentrations other than 8 mg/ml, and carriers other than 10% hydroxypropyl-b-cyclodextrin and 3% Mannitol, pH 5.9-6 can be used 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.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
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 not 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.
Conclusion
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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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654