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 .
This is a Final Office Action.
Claims 1-15, 18 and 19 are pending and claims 1-9, 18 and 19 are under examination. Claims 10-15 are withdrawn based on the unity of invention.
Election/Restrictions
Applicant's election without traverse of Group I in the reply filed on October 30, 2025 is acknowledged. Group I, drawn to a process for preparing trenbolone acetate, embraced by claims 1-9, 18 and 19 was elected by Applicant.
Claim Objections
Claim 19 is objected to because of the following informalities: the phrase, “the steps are carried out one-pot.” should be replaced with “the previous step is carried out in one-pot.” Appropriate correction is required.
The objection was not addressed and thus, is maintained.
Claim Rejections - 35 USC § 112
The rejection of claims 3, 7 and 8 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “the particle size distribution in the range,” is withdrawn based on the amendments.
The rejection of claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase, “in the range,” is withdrawn based on the amendments.
The rejection of claim 8 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase, “the phrase, “the obtained Trenbolone Acetate of formula (I) having,” is withdrawn based on the amendments.
The rejection of claim 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “the previous step,“ is withdrawn based on the amendments.
The rejection of claim 19 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the process of claim 18 carried out in one-pot is withdrawn.
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 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-9, 18 and 19 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Roussel UCLAF (GB 1035683, cited on the IDS) in view of Hardwood et al. ((Experimental Organic Chemistry, Standard and Microscale, 2nd Edition, 1998, pp. 131-143), and Johnson et al. (WO 2007106768, cited on the IDS).
The present application claims a process of making trenbolone acetate comprising crystallizing trenbolone acetate with a C2-C5 alkyl alcohol (see claim 2 for isopropanol) or a mixture thereof. Claim 3 introduces a seeding step for the crystallization to obtain a particular crystal shape and size as noted in the dependent claims.
The ‘683 patent teaches a crystallization of trenbolone acetate utilizing isopropyl ether and hexane, see Example 3, page 7, left-hand column, lines 66-67. The reference further teaches that the compound is soluble in alcohol, see page 7, left-hand column, line 74. The ‘683 patent does not prepare trenbolone acetate in an C2-C5 alkyl alcohol or a mixture thereof.
Crystallizations are considered routine and conventional for isolating and/or purifying organic compounds as these techniques are taught in organic classes and textbooks, see the Hardwood reference, that provides guidance for determining solvents (including anti-solvents), temperatures, seeding, etc. Accordingly, this type of modification would have been well within the purview of the skilled artisan, unless there is evidence to the contrary.
Johnson et al. teach, “[A] process, for the production of crystalline particles of an active organic compound The process includes the steps of generating a micro-seed by a wet-milling process and subjecting the micro-seed to a crystallization process. The resulting crystalline particles have a mean particle size of less than about 100 μm. The present invention also provides for a pharmaceutical composition which includes the crystalline particles produced by the method described herein and a pharmaceutically acceptable carrier.,” see abstract. The further teaches, “In an effort to control the morphologic properties of the final product, it is a trend in One particle engineering to use seed particles of the product to provide a template for crystal growth during crystallization. Seeding can help control the particle size, crystal form, and chemical purity by limiting the supersaturation,” see page 3, paragraph [0007]. The reference teaches the seeding technique in claim 3 to obtain the claimed particle sizes.
Claim 9 is drawn to a specific crystal structure of irregular hexagon plates. The ‘683 patent is silent on the type of crystal produced during the crystallization. However, following the procedure in the Johnson publication, a person skilled in art would inherently obtain the specific crystal structure as claimed.
The ‘683 patent teaches the step found in claim 18 that converts the OH-steroid to the acetyl ester steroid of trenbolone acetate and the reaction is done in one-pot (see claim 19), see Example 3, page 7, left-hand column, lines 66-67.
Moreover, generally, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such variable is critical. "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." In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955). The adjustment of particular conventional working conditions (e.g., determining result effective solvents taught by the cited references), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan.
Therefore, the claimed process is found obvious over the ‘683 patent that teaches the crystallization of trenbolone acetate from isopropyl ether and hexane. The reference further teaches trenbolone acetate is soluble in alcohols, which may replace the isopropyl ether solvent for the crystallization while utilizing the teachings of Hardwood and Johnson to seed the crystallization and further obtain a particular size and form of crystal.
To overcome the rejection, unexpected results, commensurate in scope with the claims, may be submitted.
Claims 1-9, 18 and 19 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Roussel UCLAF (GB 1035683, cited on the IDS) in view of Hardwood et al. ((Experimental Organic Chemistry, Standard and Microscale, 2nd Edition, 1998, pp. 131-143), Johnson et al. (WO 2007106768, cited on the IDS) and Borodi et al. (Journal of Molecular Structure, 2020, 1-9, cited on the IDS).
The previous 103 rejection is incorporated here.
Borodi et al. teach a crystal structure of trenbolone acetate with the same crystal x-ray spectrum as currently disclosed. The reference does not teach a process of how the trenbolone acetate was synthesized. While the x-ray diffraction pattern is not an indicator of the particle size, the reference does provide support that the same crystal structure was previously made.
Therefore, the claimed process is found obvious over the ‘683 patent that teaches trenbolone acetate is soluble in alcohols, which may replace the isopropyl ether solvent for the crystallization while utilizing the teachings of Hardwood and Johnson to seed the crystallization and further obtain a particular size and form of crystal.
To overcome the rejection, unexpected results, commensurate in scope with the claims, may be submitted.
Applicant traverses by stating, “The asserted combination does not teach or suggest the claimed trenbolone-acetate crystallization process. Claim 1 requires crystallizing trenbolone acetate with a C2-C5 alkyl alcohol or mixture thereof.”
This is not persuasive.
Applicant states, “Roussel UCLAF does not disclose or suggest the claimed alcohol crystallization. In Example 3, Roussel UCLAF obtains trenbolone acetate only after purification though a column of magnesium silicate and "recrystallization from isopropyl ether and hexane," and describes the product as "colourless flakes" that are "soluble in alcohol." Those disclosures are materially different from crystallizing trenbolone acetate with a C2-C5 alkyl alcohol as required by claim 1. A statement that the compound is soluble in alcohol does not provide a teaching or reason to replace Roussel UCLAF's disclosed isopropyl ether/hexane recrystallization system with an
alcohol crystallization system, much less to do so for the purpose of obtaining the claimed particle-size distribution and irregular hexagon plates crystal habit.”
Claim 1 is drawn to a process comprising crystallizing trenbolone acetate with a C2-C5 alkyl alcohol or mixture thereof. The term “comprising” allows for any other purification methods and claim 1 does require any particle size. A person skilled in the art would use the “soluble in alcohol” as another solvent for crystallization, while using the hexane as an anti-solvent based on the teachings in Hardwoood since organic chemists are always looking for ways to increase yields of products.
Applicant further states, “Harwood et al. does not cure that deficiency. Harwood et al. provides general laboratory guidance for crystallization, including that choosing a crystallization solvent "is not always easy," that preliminary solubility tests may be needed, and that a seed crystal may be added when crystallization does not occur. Such general guidance may show that crystallization techniques were known, but it does not supply the required articulated reason, under KSR, to modify Roussel UCLAF's specific trenbolone acetate recrystallization from isopropyl ether and hexane into the claimed crystallization with a C2-C5 alkyl alcohol. Nor does it provide a reasonable expectation that such a solvent substitution would produce the claimed trenbolone acetate morphology or the process results recited in the dependent claims.”
Indeed, the Hardwood reference is provided for general laboratory guidance for crystallizations since this process is conventional in an organic lab. Hardwood teaches different solvents are used for crystallizations and one can be substituted for another.
Applicant notes, “Johnson et al. likewise does not teach the claimed trenbolone-acetate-specific seeded crystallization sequence. Johnson states generally that seeding can help control "particle size, crystal form, and chemical purity" by limiting supersaturation, and describes generating a micro- seed by wet milling, where the micro-seed has a mean particle size of about 0.1 to about 20 µm and the resulting crystalline particles have a mean particle size of less than 100 µm. Johnson, paragraphs [0007] and [0012]. Those disclosures are generic to crystalline particles of an organic active compound and are not directed to trenbolone acetate, Roussel UCLAF's ether/hexane recrystallization, the claimed D50 seed ranges, the claimed ordered cooling/filtering/suspension/filtering sequence, or the irregular hexagon plates crystal habit recited in claim 9. At most, Johnson shows that seeding is one known crystallization tool; it does not establish that applying Johnson's wet-milled micro-seed concept to Roussel UCLAF would necessarily or predictably yield the claimed trenbolone acetate process product.”
Indeed, the Johnson reference is provided for a general teaching on how to control particle size distribution during crystallizations.
Applicant further notes, “The inherency rationale for claim 9 is also unsupported. Inherency cannot be established by mere possibility or probability; the missing limitation must necessarily result from the prior-art combination. Here, the record does not show that replacing Roussel UCLAF's isopropyl ether/hexane recrystallization with an alcohol crystallization and adding Johnson's generic seeding approach would necessarily produce trenbolone acetate having irregular hexagon plates crystal habit. The present specification underscores why that conclusion is not inherent: trenbolone acetate crystallized using solvents different from C2-C5 alkyl alcohols forms different morphologies, including soft polycrystalline agglomerates, while crystallization with C2-C5 alkyl alcohols provides mainly thin irregular hexagon plates. See specification paragraphs [0124]-[0127] and [0266]-[0269], and FIGS. 3, 5, and 7.”
The inherency is based on the wherein clause. The wherein clause of claim 9 does not require additional steps to be performed and simply expresses the outcome of the crystallization result of carrying the process made obvious by the prior art. MPEP 2111.04 states: “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) “ adapted to ” or “adapted for ” clauses;
(B) “ wherein ” clauses; and
(C) “ whereby ” clauses.
The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “whereby’ clause states a condition that is material to patentability; it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat ’l Ass ’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” (Emphasis added).
Applicant contends, “Borodi et al. does not remedy these process deficiencies. Borodi's abstract states that the crystal structures of trenbolone acetate and trenbolone hexahydrobenzylcarbonate were determined by X-ray single crystal diffraction and shown to belong to the monoclinic P21 space group. That structural characterization does not disclose how to prepare trenbolone acetate by crystallization with a C2-C5 alkyl alcohol, does not disclose the claimed seeded process steps or D50 seed ranges, and does not establish that the claimed irregular hexagon plates crystal habit would inherently result from the Examiner's proposed combination. Thus, even with Borodi added, the rejection still relies on hindsight reconstruction rather than a teaching, suggestion, or articulated reason supported by the cited record.”
Indeed, the Borodi reference does not provide the process by which the crystal structure of trenbolone acetate was prepared. However, the reference does provide support that the same crystal structure was previously made. Therefore, a person skilled in the art can determine the solvents required to obtain said crystal by routine and conventional methods, which is well within the purview of the skilled artisan.
Thus, 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 SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
