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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/12/2025 has been entered.
Claim Status
Claims 1-2, 6, 8-10, 13, 15, and 18-27 are pending. No claims were amended, canceled, or added in the Reply filed 9/12/2025. Claims 8-10, 13, and 20-24 remain withdrawn as directed to a non-elected invention. Claims 1-2, 6, 15, 18-19, and 25-27 are presently considered.
Election/Restrictions
Applicant's election with traverse of Group I1 (claims 1-3, 6, and 15-19) in the reply filed on 9/19/2024 was previously acknowledged and not found persuasive for reasons of record (see, e.g., Action mailed 11/14/2024 at pages 3-4); and the requirement was made final.
The elected invention is understood to be compositions and methods of treating (or preventing) pain and ADHD, wherein all claims require the compound of AM-9, which is identified as “Amphetamine-arginine-glycine-acetate”, and is shown at claim 1.
Following extensive search and examination, the originally elected species has been deemed obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A), examination has not been extended to non-elected species at this time, and claims directed to non-elected species are withdrawn.
Claims 8-10, 13, and 20-24 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 9/19/2024.
During the search and examination of the originally elected species, art pertinent to other non-elected species was incidentally discovered. Although examination has not been extended beyond the non-elected species identified above per MPEP § 803.02, as a courtesy to the Applicant, this art has been applied below.
Claims 1-2, 6, 15, 18-19, and 25-27 are presently considered.
Examiner Notes
Examiner’s understanding was that a Declaration would be filed supporting a conclusion of unexpected results (see, e.g., Interview Summaries mailed 8/25/2025, 9/09/2025, and 9/16/2025).
As a courtesy, Examiner called Khin K. Chin on 10/3/2025 and noted that Examination was about to begin, and the Examiner noted that a declaration had not yet been submitted at that time. Examiner notes that no declaration was filed prior to 10/20/2025. Accordingly, examination has proceeded in view of the response filed 9/12/2025 and in the absence of a declaration.
Priority
The priority claim to US Provisional 62/814,630 (filed 3/06/2019) is acknowledged.
Information Disclosure Statement
The IDS filed 9/12/2025 is acknowledged and presently considered.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope. AM-9 is reasonably inferred be the compound shown at claim 1, which corresponds to CAS No. 2489219-47-6, which has the structure of
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and is associated with the instant Application in the CAS Registry (see, e.g., WO2020/181000 A1 at Substance Table beginning at page 85; note that WO’000 corresponds to the instant PG Pub of US 20220175699).
Claims 15 and 18-19 are directed to broad methods of “treating” ADHD, wherein the method comprises the administration of a prodrug AM-9, wherein administration includes all routes of administration2, wherein administration utilizes an unspecified “effective amount”3, and wherein the subject is a “patient in need thereof”. The term “preventing” was previously removed (see, e.g., Action mailed 11/14/2024 at 4-5).
Additional claim interpretations are set forth below.
Maintained Claim Rejections
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 1-2, 6, 15, 18-19, and 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over WO2011/133347A1 (Jenkins et al., Oct. 27, 2011; cited in previous action).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
WO’347 discloses and pertains to a genus of trypsin-cleavable amphetamine prodrugs suitable for use in the treatment of ADHD and other conditions4. Regarding instant claims 1-3, 6, 15, 18-19, 25-27, and the structure of trypsin-cleavable amphetamine prodrugs generally, WO’347 teaches and discloses a genus of trypsin-cleavable amphetamine prodrugs that encompasses the structure of instant AM-9, namely a genus of compounds of AM-(I):
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WO’347 identifies that R1 may be the sidechain of arginine5, and that R2 may be any “substituted acyl” or R4 moiety. “Substitution” is broadly described6, and R4 is defined to comprise any peptide comprising 1-100 amino acids, so long as the “terminal end of the peptide is N-acylated, wherein the acyl group is acetyl”7, which includes Acetylglycine, and wherein the genus includes stereoisomers, enantiomers, and diastereomers of AM-(I)8. Therefore, the instantly claimed compound of AM-9 is a species of the prior art genus of trypsin-cleavable amphetamine prodrugs taught and disclosed by WO’347. Regarding instant claims 2 and 6, and the combination of a trypsin-cleavable amphetamine prodrugs in combination with a trypsin inhibitor, WO’347 direct artisans to a pharmaceutical compositions comprising pharmaceutically acceptable carriers and an effective amount of the disclosed compounds (see, e.g., WO’347 at claim 11), wherein such compositions are reasonably understood to include trypsin inhibitors (see, e.g., WO’347 at claim 12). Accordingly, the combination of trypsin-cleavable amphetamine prodrugs in combination with trypsin inhibitors was taught, disclosed, and practiced in the prior art, and wherein it was already known that such combinations would desirably permit artisans to control the “enzymatically-controlled release of amphetamine or the amphetamine analog from the amphetamine prodrug following ingestion”9. Regarding instant claims 15, 18-19, and 25-27, and methods of “treating” ADHD, and “pain” 10 associated with brain injuries, CFS, narcolepsy, and obesity, WO’347 teaches that trypsin-cleavable amphetamine prodrugs can be utilized to treat multiple conditions, including brain injuries, ADHD, Chronic Fatigue Syndrome (CFS), narcolepsy, obesity, etc., wherein “treatment” would include any associated “pain” (e.g., “brain injuries” is reasonably inclusive of symptoms including headaches, migraines, etc.)11. Critically, WO’347 discloses that such treatments of the same patient populations using trypsin-cleavable amphetamine prodrugs alone or in combination with trypsin inhibitors could be practiced at the same concentrations disclosed on the instant record12,13. Accordingly, the prior art teaches the treatment of the same patient populations using the same type of compound (i.e., trypsin-cleavable amphetamine prodrugs), at the same “effective amount”.
WO’347 differs from the instant claims as follows: Although WO’347 discloses a genus of trypsin-cleavable amphetamine prodrugs usable in combination with trypsin inhibitors in the same methods as instantly claimed, having the general structure of
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,
WO’347 does not teach or disclose the exact compound of AM-9 as presently claimed, wherein R1 is the side chain of arginine, and R2 is N-acetylglycine (-C(O)-CH2-NH-C(O)CH3). Therefore, the relevant issue is whether or not the claimed compound of AM-9 renders the instant claim scope patentably distinct relative to the prior art.
Per MPEP § 2144.08 and § 2144.09, obviousness may be established in view of a prior art genus that discloses a claimed species (see, e.g., MPEP § 2144.08) or in view of close structural similarity between chemical analogues (see, e.g., MPEP § 2144.09). Specifically, MPEP § 2144.09(I) explains that “A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities”.
The prior art genus is applicable to amphetamine and amphetamine analogs: WO’347 clearly inform artisans that the disclosure is applicable to amphetamine and amphetamine analogs (see, e.g., WO’347 at 20 at line 18 to p. 22 at line 29), and stereoisomers, enantiomers, and diastereomers of AM-114.
The prior art directs artisans to utilize the sidechain of arginine at position R1 of AM-(I): WO’347 directs artisans to utilize trypsin-cleavable amphetamine prodrugs having the general structure of
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,
wherein R1 is the sidechain of arginine15, wherein R2 is a “substituted acyl” having an “acetyl” moiety, in view of the claims16, and in view of the exemplified embodiment of Compound AM-1:
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17,18,
and stereoisomers, enantiomers, and diastereomers of AM-119. Relative to the closest prior art of record, namely Compound AM-1, the claimed structure of AM-9 differs with respect to the R2 position of Compound AM-1, because AM-9 has an N-acetylglycine (-C(O)-CH2-NH-C(O)CH3) at the R2 position rather than an acetyl moiety. However, this difference would not alter the predicted and expected results established in view of WO’347 because WO’347 explicitly identifies that the R2 position may be any “substituted acyl” moiety20, wherein “such substitutions” fully encompass structures including N-acetylglycine 21. In addition or alternatively, WO’347 identifies that the R2 position may actually be an R4 moiety, wherein the R4 moiety may be any peptide comprising 1-100 amino acids, so long as the “terminal end of the peptide is N-acylated, wherein the acyl group is acetyl….”22, including stereoisomers, enantiomers, and diastereomers thereof23. Accordingly, an artisan would have been readily directed to utilize variants of variants of Compound AM-1 or isomers thereof, having an R4 moiety that could optionally comprise 1-100 amino acids, so long as the terminal amino acid had an acetyl moiety:
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wherein “Xaa” as shown represents an optional 1-100 L-amino acids, wherein the “terminal end of the peptide is N-acylated, wherein the acyl group is acetyl…”24.
Per MPEP § 2143.03, one of ordinary skill in the art would readily appreciate in view of the disclosure of WO’347 that the presence or absence of additional amino acids at position R2 was not reasonably expected to abrogate activity of any particular species of trypsin-cleavable amphetamine prodrugs, so long as position R2 comprised a terminal acetyl moiety as present in Compound AM-1 (see, e.g., MPEP § 2144.08(II)(A). Therefore, although highly variable, the exact residues at position R2 would be understood to not to be critical to the overall function of members of the genus taught by WO’347 or to stereoisomers, enantiomers, and diastereomers of AM-125, because an artisan would readily appreciate that 1-100 amino acids could be inserted at the position to create functional equivalents. Accordingly, all species of the prior art genus would be reasonably presumed to be functional equivalents relative to Compound AM-1 of WO’347, and Compound AM-1 of WO’347 is therefore understood to be a highly similar chemical analog of any compound within the genus of
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All members of the genus would be reasonably expected to exhibit the same functions and have the same utility as Compound AM-1 of WO’347 at least because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), and here it discloses that the entire genus are trypsin-cleavable amphetamine prodrugs, usable with trypsin inhibitors, to treat the same conditions presently claimed at the same concentrations (see discussion above) (see also MPEP § 2144.09).
In sum, here the “inventive aspect” of the instantly claimed invention appears to simply amount to the selection of a species within the prior art genus, amounting to a permissible alteration of Compound AM-1 at position R2 using only modifications and permissible arrangements already taught in the genus of trypsin-cleavable amphetamine prodrugs disclosed by WO’347, wherein such trypsin-cleavable amphetamine prodrugs are utilized alone or in combination with trypsin inhibitors, and wherein such compositions are merely utilized to treat the same prior art patient populations at the same concentration ranges26,27, to achieve the same or highly similar effect. No unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been established on record showing or alleging that AM-9 does anything more than expected of other trypsin-cleavable amphetamine prodrugs within the scope of WO’347. Accordingly, all properties and parameters of AM-9 appear predictable and expected because they appear to only be the same, exact expectations taught and disclosed by WO’347 for all other trypsin-cleavable amphetamine prodrugs within the scope of AM-(I), including Compound AM-1. Accordingly, this supports a determination of obviousness because
"[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results."
(KSR at 415-16, 82 USPQ2d at 1395),
and because
"[t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result."
(KSR at 415-16, 82 USPQ2d at 1395; see also MPEP § 2141(I)).
Simply modifying the prior art genus of WO’347 exactly as taught by WO’347 to achieve a species wholly within the subgenera of the prior art, wherein the species only appears to do the exact same things taught, predicted, expected, and identified by WO’347, at the same exact concentration range as any other functional equivalent taught by WO’347, is not surprising or non-obvious, but is instead merely the exact result that would be predicted and expected for all members of the prior art genus of functional equivalents. because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): Per MPEP § 2144.09(I), a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities; likewise, WO’347 discloses a genus of functional equivalents and exemplifies a highly similar chemical analog of Compound AM-1 relative to instantly claimed AM-9, wherein WO’347 explicitly discloses that such chemical compounds have essentially identical utility, namely the compounds are such trypsin-cleavable amphetamine prodrugs usable to treat the same patient populations via administration of the same “effective” amounts (see, e.g., MPEP §§ 2144.08, 2144.09). In addition, or alternatively, the claimed inventions amount to a mere substitution of functional equivalents, namely trypsin-cleavable amphetamine prodrugs within the narrow genus of AM-(I) and variants of Compound AM-1 as taught and suggested by WO’347, wherein the substitution of an equivalent of Compound AM-1 would merely yield only the expected and predicted results taught and suggested by the prior art, namely the same results obtained with Compound AM-1 (see, e.g., MPEP § 2144.06(II)).
Zero evidence of any unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been disclosed or taught by the prior art have been clearly identified on record. Applicant is advised that AM-1 of WO’347 is the closest prior art of record in view of WO’347. Evidence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 could rebut the instant rejection.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the biochemical arts to make, use, and synthesize all species within the prior art genus of AM-(I), including variants of Compound AM-1.
Accordingly, claims 1-2, 6, 15, 18-19, and 25-27 are rejected.
Response to Arguments
Applicant's arguments filed 9/12/2025 have been fully considered but they are not persuasive.
Examiner notes that no amendments were filed in the RCE filed 9/12/2025, and the rejections of record have been maintained. Accordingly, the Examiner’s prior responses of record, including in the interviews of record (see, e.g., Interview Summaries mailed 8/25/2025, 9/09/2025, and 9/16/2025), remain pertinent and are incorporated herein.
Applicant traverses the rejection under 35 USC 103 at pages 6-14 of the Reply (see, e.g., Reply filed 9/12/2025 at 6 at § “Rejections Under § 103(a)” to 14 at 1st partial ¶; see also Reply filed 2/10/2025 at 6 at § “Rejections Under § 103(a)” to p. 10 at 2nd ¶).
Undisputed issues: It is the Examiner’s understanding that Applicant again fails to dispute the Examiner’s rationales for supporting a determination of obviousness under MPEP §§ 2144.08 and 2144.09; or any underlying facts relied upon by the Examiner. Therefore, it is the Examiner’s understanding that Applicant does not dispute that the claimed invention is prima facie obvious in view of the prior art. Rather, it is the Examiner’s understanding that Applicant’s argument is that the claims are allowable in view of secondary considerations, namely alleged unexpected results (see, e.g., Reply filed 9/12/2025 at 6 at 3rd full ¶ to 14 at 1st partial ¶; see, e.g., Reply filed 2/10/2025 at 6 at § “Rejections Under § 103(a)” to p. 10 at 2nd ¶; see esp. id. at 7 at 1st and 2nd ¶¶). The allegations of unexpected results are discussed below. However, it is presently undisputed that the claimed subject matter is prima facie obvious for reasons of record.
Allegations of Unexpected Results
As an initial matter, a showing of unexpected results sufficient to rebut prima facie obviousness must satisfy the requirements of MPEP §716, §716.01, and §716.02. In brief, to establish unexpected results, the proffered evidence must establish that the expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), which is fully explained (see, e.g., MPEP § 716.02(b)(II)), commensurate in scope with the claimed invention (see, e.g., MPEP § 716.02(d)), and wherein a comparison of the claimed invention with the closest prior art of record is provided (see, e.g., MPEP § 716.02(e)). Furthermore, even if evidence satisfying MPEP §§ 716.02, 716.02(a), 716.02(b), 716.02(d), and 716.02(e) is set forth on record, such evidence may not be sufficient to rebut prima facie obviousness because the evidence of expected and unexpected results must be weighed (see, e.g., MPEP § 716.02(c)(I)) and the totality of the record considered (see, e.g., MPEP § 716.02(f)), including teachings in the prior art and evidence of expected results which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)).
In the interviews of record the Examiner discussed the proffered evidence of record in the context of an unsigned declaration, and identified multiple deficiencies in the proffered data (see, e.g., Interview Summaries mailed 8/25/2025, 9/09/2025, and 9/16/2025). For example, the data lacked statistical significance as required by MPEP § 716.02(b), the data was not fully explained (e.g., error bars could represent SD, SEM, CI95, etc.) as required by MPEP § 716.02(b), the data was not commensurate in scope with the claim scope as required by MPEP § 716.02(d) (see Interview Summary mailed 9/9/2025, explaining that the data was limited to oral administration only), and that the proffered data appeared to confirm the same applications of the same genus of structures to the same patient population to achieve the same effect, which weighed in favor of obviousness per MPEP § 716.02(c)(II). These deficiencies were not corrected or clearly addressed in the response filed 9/12/2025, and no signed declaration was actually signed and averred in the response filed 9/12/2025. Accordingly, the discussions of deficiencies of the proffered data as set forth in the Interview Summaries are incorporated into the instant response.
The Reply filed 9/12/2025 sets forth data and arguments alleging the existence of unexpected results, namely an allegation that AM-9 is a “rapid release” agent relative to AM-1 because it allegedly has a statistically different Tmax relative to the closest prior art of record (see, e.g., Reply filed 9/12/2025 at 7 at 1st ¶ to 8 at 1st full ¶). The proffered data has been reviewed, and the Examiner’s position is that the proffered data and explanations do not satisfy the requirements of MPEP §§ 716, 716.01, or 716.02 for at the following reasons:
First, the proffered data fails to appear in the form of a declaration (see, e.g., MPEP §§ 716, 716.01). No statements are averred by a Declarant. Zero charts or Tables shown in the Reply to support a determination of unexpected results actually appear in the originally filed disclosure. Such data appears to originate from unsigned declarations addressed during interviews, but no actual averred statement by a declaration appears on record regarding the novel data. Accordingly, it is unclear if the data and accompanying statements are accurate or representative of the claimed invention. Arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), which is relevant because MPEP § 716 requires actual evidence.
Second, the proffered data fails to satisfy the requirements of MPEP § 716.02(d), because the proffered data, even considered in the light most favorable to the Applicant, is not commensurate in scope with the pending claim scope. Specifically, the instant claims are not limited to (i) oral administration, (ii) concentrations of 0.6 mg/kg to 27.7 mg/kg, (iii) subjects of rats fasted overnight, (v) samples obtained at 0.167, 0.333, 0.5, 0.667, 0.833, 1, 2, 4, 5, and 8 hours post-treatment, or (vi) pharmaceutical formulations comprising 0.1% formic acid (see, e.g., Spec. filed 09/02/2021 at 54 at Example 1 to p. 56 at 2nd full ¶; see, e.g., Reply filed 9/12/2025 at 8 at 1st full ¶). Instead, the pending claims encompass all routes of administration28, an unspecified dosage at an “effective amount”29, to any subject (e.g., humans, mammals, non-mammals), using any pharmaceutical formulation30, and wherein the pharmaceutical formulation utilized may vary substantially. This is pertinent because the prior art is not limited to oral delivery in fed or fasted patients, and explicitly teaches intravenous injections (see, e.g., WO’347 at Examples 8, 12, 21, and 22). Accordingly, the proffered data fails to satisfy the requirements of MPEP § 716.02(d).
Accordingly, the proffered data is insufficient to establish unexpected results commensurate in scope with the requirements set forth at MPEP §§ 716, 716.01, and 716.02. As a courtesy to the Applicant, and to facilitate compact prosecution, additional deficiencies are addressed below:
Third, it is the Examiner’s understanding that Applicant attempts to use an “indirect comparative test” (see, e.g., MPEP § 716.02(b)(III)) between their disclosed data, and previously published data in WO2011/133347A1. Although “indirect comparisons” are permissible (MPEP § 716.02(b)(III)), such comparisons must satisfy the requirements of MPEP § 716.02, including statistical significance. Regarding indirect comparisons used in the biological arts, the art states that “readers of indirect comparisons should exercise caution and skepticism when interpreting results from indirect comparisons” because indirect comparisons “are consistently underpowered” (see, e.g., Mills31 at abs, 8 at col I-II at bridging ¶, 8 at col II at last ¶). Furthermore, the prior art identifies that the validity of adjusted indirect comparisons “depends on the internal validity and similarity of the included trials” (see, e.g., Song32 at abs). The art identifies how to perform statistically valid indirect comparisons (see, e.g., Cucherat33, passim). Specifically, Cucherat identifies that “naïve indirect comparisons” are “unsuitable methods”, “are not adequate”, and “should not be called indirect comparisons” (Cucherat at 6 at § Statistical Methods”). Cucherat identifies that “naïve comparisons” are invalid (see, e.g., Cucherat at 16 at §§4, 4.1, 4.1.1), and further identifies that although it “may appear as natural way of thinking while comparing two active treatments” (id.), that naïve indirect comparisons are “methodologically completely invalid” and “one of the sources of current mistrust with regard to indirect comparisons” (see, e.g., Cucherat at 18 at 1st partial ¶). Cucherat identifies valid methodologies required for proper indirect comparisons (see, e.g., id. at § 4.2, discussing required calculations). In the instant case, the proffered indirect comparison appears to be a “naïve comparison” because the compared data lacks any identified common comparator, no actual test for statistical significance was actually performed at all, and the conditions tested for the samples is not identified as identical. Accordingly, the rationale provided by the Applicant “may appear as [a] natural way of thinking while comparing two active treatments” (see, e.g., Cucherat at 16 at §§4, 4.1, 4.1.1), such naïve indirect comparisons are “methodologically completely invalid” (see, e.g., Cucherat at 18 at 1st partial ¶). Accordingly, no evidence of a difference of both statistical and practical significance has been established in view of the instant record. This means the alleged differences among compounds may lack statistical significance and merely fall within the range of experimental error. Accordingly, such overlapping error bars, as noted above, combined with what appears to be a naïve indirect comparison casts substantial doubt on the allegations of statistical significance at Table 1 on page 11 of the Reply. Accordingly, the proffered data appears to be a naïve indirect comparisons, which is recognized in the art as “methodologically completely invalid” (see, e.g., Cucherat at 18 at 1st partial ¶).
Fourth, even assuming arguendo that the comparisons are valid, the proffered data does not appear to actually properly assay a “Tmax” value as recognized in the prior art. Specifically, the proffered data at the graphs and Table 1 appears to use an arbitrary definition for “Tmax” that does not actually reflect the art-recognized meaning of the term (see, e.g., Reply filed 9/12/2025 at Table 1 on 11). This is problematic because a “Tmax” is recognized in the art as the “time to reach the maximum concentration (Cmax)”, wherein “the drug absorption rate equals the drug elimination rate”, and is defined for single-dose, orally administered drugs as
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Wherein ka is the absorption rate constant, and ke is the elimination rate constant (see search notes, showing common Pharmacokinetic equations). However, no discussion or calculations regarding Cmax, drug absorption rate, drug elimination rate, etc., etc., is actually provided in the response. This raises a substantial concern, namely “what is Applicant calling ‘Tmax’ at Table 1?”. At Table 1, the Applicant appears to simply and arbitrarily label an arbitrarily assayed time point corresponding to the highest, discrete plasma concentration actually assayed, without any additional consideration or calculations regarding (i) error, (ii) drug absorption rates, (iii) Cmax, (iv) drug elimination rates, etc., etc. The scientific and logical basis of such an approach is unclear on record because such an arbitrary methodology would inherently yield highly variable and arbitrarily identified “Tmax” determinations from lab to lab for the same chemical compounds. For example, such an arbitrary methodology would report a different Tmax value if only 1 sample was assayed every two hours, every one hour, every half hour, every 15 minutes, or every minute. Accordingly, rather than a Tmax value for a single oral administration, defined as
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the calculations at Table 1 appear to utilize a number that is not a Tmax value at all. Applicant fails to address how the values arbitrarily selected as “Tmax” values at Table 1 actually satisfy the art-recognized definition of a Tmax value, and such values appear to be an arbitrarily selected times selected without consideration for error, Ka, Ke, Cmax, AUC, etc., etc., based upon a ill-described methodology that would presumably vary from one lab to another. Accordingly, all calculations and assumptions premised upon the assumption that the “Tmax” values of Table 1 are actually “Tmax” values fail to satisfy the requirements of MPEP § 716.02(b), because the proffered data was not explained as required, and in view of the current record such timepoints do not reasonably appear to actually correspond to a properly calculated, error-free, singular, art-recognized Tmax value.
Fifth, even assuming arguendo that the comparisons are valid, and assuming arguendo that the alleged “Tmax” values are actually art-recognized Tmax values, the proffered data would continue to be insufficient to establish unexpected results because the proffered data does not support the existence of a singular “Tmax” value as set forth at Table 1 of the Reply and presumably utilized in the Mann-Whitney U Test to determine a p-value. Here, Applicant asserts that the error bars represent “±1 standard error of the mean” (see, e.g., Reply filed 9/12/2025 at 11 at 1st full ¶). This is pertinent because the proffered data is limited, but shows substantially overlapping concentrations are multiple time points:
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These are representative but non-exhaustive illustrations of a systemic issue with the proffered data. The SEM error bars substantially and materially overlap over an extensive amount of time, which indicates that the time points do not statistically differ with respect to concentration across the entire range of overlapping data points. The is pertinent because the art teaches that
“When SEM bars for the two groups overlap, and the sample sizes are equal, you can be sure the difference between the two means is not statistically significant (P>-0.05)”
(see, e.g., Graphpad_ErrorBars34 at 1, emphasis added).
Accordingly, such data does not reasonably show or suggest a statistically significant difference exists between the Tmax of AM-9 and AM-1, because the data at best suggests that Tmax occurs somewhere within an overlapping range of times for both substances. At best, this means that, for example, at the Graph at the bottom of page 9 of the Reply, that the “Tmax” for AM-9 occurs between “about” 0.5 and “about” 1 hour, and the “Tmax” for AM-1 occurs at between “about” 1 hour and “about” 2 hours (see, e.g., Reply filed 9/12/2025 at 9 at final ¶). Since the “Tmax” is at best shown to be statistically undiscernible over a wide time range, the Applicant’s arbitrary selection of a specific time point to utilize as a “Tmax” at Table 1 appears to be scientifically and mathematically unsupported, and the Applicant’s choice is not explained on record (i.e., the proffered data does not satisfy their burden under MPEP § 716.02(b) to fully explain all data). This is relevant because since the SEM bars overlap, no single time shown reasonably corresponds to a singular Tmax value, because “the difference between the two means is not statistically significant”35. Accordingly, the proffered analysis at Table 1 fails to meaningfully and practically represent the actual data shown in the graphs, and therefore such analysis fails to satisfy MPEP §§ 716.02(a), (b),(d), and (e) by fully explaining the proffered data and providing unambiguous data showing practical and statistical significance.
Sixth, even assuming arguendo that the comparisons were valid, assuming arguendo that the alleged “Tmax” values are actually art-recognized Tmax values, and assuming arguendo that a singular “Tmax” value could be identified from the statistically indiscernible ranges of values shown in the graphs, the proffered data would continue to be insufficient to establish unexpected results because it is unclear how the Mann-Whitney U test has been properly applied. It is the Examiner’s understanding that Applicant alleges that the p values of the proffered data (except for the 6 mg/kg dosage) is statistically significant with p values of less than 0.05 (see, e.g., Reply filed 9/12/2025 at Table 1 on 11), and that such p-values were determined using the Mann-Whitney U test (see id. at 11 at 1st full ¶). However, the Examiner has been unable to replicate such p-values for the proffered data, and it is prima facie unclear how the data was actually processed, what numbers were actually compared, etc., and therefore it is unclear what exact conclusion can be drawn from the reported p-values. Accordingly, the data does not appear to satisfy the requirement of MPEP § 716.02(b) to fully explain the proffered data. Examiner notes that the proffered conclusions of statistical significance also raise substantial concerns because the art teaches that
If you have small samples, the Mann-Whitney test has little power. In fact, if the total sample size is seven or less, the Mann-Whitney test will always give a P value greater than 0.05 no matter how much the groups differ.
(see, e.g., Graphpad_Mann-Whitney36 at 1, emphasis added).
This is pertinent because the sample size appears to be less than seven for all proffered data for AM-1 (i.e., all tables show only five tested datapoints for AM-1), and therefore the expected result of so few data points is a P value greater than 0.05 (i.e., the data would not be significant using a Mann-Whitney test based on the current explanations of record) simply based upon the small sample size. Accordingly, in the absence of further explanations and averred statements, such data does not appear to support conclusions of statistical significance as presently alleged. Accordingly, such data cannot be reasonably said to satisfy the requirements for fully explaining proffered data per MPEP § 716.02(b).
Seventh, even assuming arguendo that the comparisons were valid, assuming arguendo that the alleged “Tmax” values are actually art-recognized Tmax values, and assuming arguendo that a singular “Tmax” value could be identified from the statistically indiscernible ranges of values shown in the graphs, the proffered data would continue to be insufficient to establish unexpected results because the comparison with the closest prior art of record must be statistically and practically significant (see, e.g., MPEP §§ 716.02(b), (e)), and the Applicant has the burden of explaining all proffered data (see, e.g., MPEP § 716.02(b)(II)). Notably, the error of the original data, shown by the SEM error bars, indicate that the final calculated Tmax value must contain error ranges as well. However, no statistically valid means of determining the error of the alleged Tmax value is actually provided on record, reported, or otherwise calculated. In the absence of consideration of error, no statistically significant difference between the Tmax of the prior art and the Tmax of the instantly claimed invention has actually been established. This is pertinent because calculations ascertaining the statistical significance of Tmax values are not trivial as evidenced by SchultzI37 and SchultzII38. These references identify that even for ostensibly much larger datasets, that even a delta of ±20 minutes among properly calculated Tmax values is deemed to not be clinically relevant (see, e.g., SchultzI at 8-9; see also SchultzII at 9). Here, given the lack of datapoints and the substantial overlap in SEM error bars, a proper Tmax calculation, including error, would be reasonably expected to have an error of substantially greater than ±20 minutes. This suggests that a practically and statistically significant difference in the instant case would need to be substantially greater than ±20 minutes to be clinically relevant. The examiner’s position is consistent with the data actually shown in the graphs, which clearly discloses data wherein a Cmax is not determined, but rather the Tmax and Cmax, at best, occur somewhere over a wide range of times and values (see Reply at Tables on 9, showing, e.g., at 10 mg/kg that the Tmax of AM-9 appears to occur somewhere within the range of approximately 30 minutes and 1 hour, but for AM-1 within the range of about 1 hour to 2 hours, wherein the ranges overlap at 1 hr). Accordingly, proffered calculations that fail to consider experimental error as reported, cannot be said to establish a difference between the samples that is of both practical and statistically significant importance as required by MPEP § 716.02(b), in the absence of a statistically valid method that includes consideration of the experimental error.
Eighth, per MPEP § 716.02(e)(I)-(II) and § 716.02(a), a comparison is required with the closest prior art of record, and the difference must be more than expected variation among different compounds within the prior art genus. This is pertinent because WO2011/133347A1 identifies both AM-1 and AM-2 (see, e.g., WO’347 at 63). Both differ from the instantly claimed AM-9 at a single sidechain. Furthermore, WO’347 appears to show that AM-2 has a Tmax of ~0.5 hrs at Figure 7(b):
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(see also WO’347 at Table 6 on 76, noting that Tmax±sd is reported for AM-2 as 0.625±0.25). Accordingly, relative to AM-1 and AM-2, variation in Tmax was already known in the prior art for such compounds. Accordingly, it is unclear that the proffered data shows more than the expected difference in Tmax per § 716.02(a). Per MPEP § 716.02(e)(I)-(II), AM-1 and AM-2 are equally close prior art of record, and “Showing unexpected results over one of two equally close prior art references will not rebut prima facie obviousness unless the teachings of the prior art references are sufficiently similar to each other that the testing of one showing unexpected results would provide the same information as to the other”. Here, the difference in Tmax appears to be representative of the expected differences in Tmax in such prior art structures, and the proffered data fails to address AM-2 or the apparent overlap in Tmax.
Ninth, the reported “Tmax” values for AM-1 at 24 mg/kg appear to differ substantially from the prior art reported values for Tmax for AM-1 at 24 mg. Specifically, the proffered data alleges that the “Tmax” for AM-1 at 24 mg/kg is 2.5 hours (see, e.g., Reply filed 9/12/2025 at Table 1 on 11). However, in the the prior art sharing multiple named Inventor in common, the Tmax of AM-1 at 24 mg/kg was previously reported as 0.625±0.43 hrs (see, e.g., WO’347 at Table 2 on 71, 71 at lines 5-15, Table 2 reproduced in part below:
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This is a substantial and material discrepancy in the Inventor’s prior reported Tmax for AM-1 and the instantly proffered data. Critically, a Tmax of AM-1 of 0.625±0.43 is statistically indistinguishable from the alleged “Tmax” of AM-9 as set forth in instant Table 1 of the Reply filed 9/12/2025. Applicant fails to address, acknowledge, or reconcile such differences on record, and therefore exceptionally close prior art is of record, which appears to teach and suggest that AM-1 and AM-9 lack a statistically or practically significant difference in Tmax values, but such differences are not addressed. Accordingly, in view of such conflicting data, the questionable statistical analysis provided in the proffered data of the Reply filed 9/12/2025 is reasonably subject to higher scrutiny since the previously reported value establishes that a Tmax of 0.625±0.43 is the expected and predicted result, and therefore weighs in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II), noting that expected beneficial results are evidence of obviousness rather than non-obviousness).
Tenth, per MPEP § 716.02, “any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” Here, the prior art teaches a variable genus, and therefore even if AM-1 differed from instantly claimed AM-9 under some select circumstances, it is prima facie unclear whether or not such differences merely falls well-within the variation inherent within the prior art genus, or if the difference is truly unexpected (see, e.g., MPEP § 716.02(a)). Furthermore, per MPEP § 716.02(c)(II), expected beneficial results are evidence of obviousness. Here, the prior art of WO’347 teaches and discloses that trypsin-cleavable amphetamine prodrugs are prior art elements that may be utilized or in combination with trypsin inhibitors, and identifies that such compositions are predicted and expected to treat the same prior art patient populations at the same concentration ranges39,40, as claimed, to achieve the same or highly similar effect.
Accordingly, upon weighing the objective evidence of record as required by MPEP 716.02(c)(I)-(II), the evidence of record weighs in favor of a determination of obviousness because zero evidence of unexpected results commensurate in scope with the requirements of MPEP § 716.01 and §§ 716.02 have been placed on record at this time because the proffered data fails to satisfy at least MPEP §§ 716, 716.01, 716.02(a), (b), (c), and (d) as explained above.
It is the Examiner’s understanding that Applicant makes multiple assertions that are not supported by objective, credible evidence of record. For example, Applicant alleges that “It is clear that even when taking the error bars into consideration at each of the time points that Tmax is reached at a statistically significant later time for Compound AM-1 than for Compound AM-9 for a range of dosage amounts” (see Reply filed 9/12/2025 at 11-12 at bridging ¶), “the release profile… is different …with statistical significance” (see id), “…significantly faster…” (see id), etc. Such statements are unsupported by any objective, credible evidence of record for reasons discussed in the preceding paragraph; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Furthermore, such statements are contradicted by the evidence of record, including the earlier work of multiple named common inventors, showing that the Tmax of AM-1 at 24 mg/kg was previously reported as 0.625±0.43 hrs (see, e.g., WO’347 at Table 2 on 71, 71 at lines 5-15, Table 2 reproduced in part below:
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This is a substantial and material discrepancy in the prior reported Tmax for AM-1 and the instantly proffered data, which alleges that the Tmax is 2.5 hours without error. Accordingly, such statements alleging the existence of statistical or practical significance cannot actually take the place of actual supporting evidence showing such significance, especially in view of directly contradicting evidence.
It is the Examiner’s understanding that Applicant attempts to explain why a Mann-Whitney U test was utilized (see Reply filed 9/12/2025 at 12-13 at bridging ¶). This has been fully considered but is substantially moot for reasons described above. First, the “Tmax” values apparently utilized in the Mann-Whitney U test do not appear to be “Tmax” values as utilized and defined by the prior art (i.e.,
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, or other art-recognized definitions of Tmax based upon AUC or Cmax), but instead appear to incorrectly refer to arbitrarily selected, single values corresponding to a single arbitrarily selected time value with overlapping SEM error bars with other timepoints, without explanation of how such value represents an art-recognized Tmax value. Second, the proffered conclusions of statistical significance also raise substantial concerns because the art teaches that
If you have small samples, the Mann-Whitney test has little power. In fact, if the total sample size is seven or less, the Mann-Whitney test will always give a P value greater than 0.05 no matter how much the groups differ.
(see, e.g., Graphpad_Mann-Whitney41 at 1, emphasis added).
This is pertinent because the sample size appears to be less than seven for all proffered data for AM-1 (i.e., all tables show only five tested datapoints for AM-1), and therefore the expected results is a P value greater than 0.05 (i.e., the data would not be significant using a Mann-Whitney test based on the current explanations of record) simply based upon the small sample size. Third, no assessment of error in the calculations is explained, presented, or considered, and the calculations for Tmax are non-trivial as evidenced by SchultzI42 and SchultzII43. These references identify that even for ostensibly much larger datasets, that even a delta of ±20 minutes among properly calculated Tmax values is not clinically relevant (see, e.g., SchultzI at 8-9; see also SchultzII at 9). Here, given the lack of datapoints and t