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 .
Transferred Case: The following application was transferred from the previous examiner (after a supplemental non-final Office action (4/4/25) following RCE) to the present examiner.
Extensive Interview: The examiner held an extensive interview (5/22/26) with applicant’s representative (AR) on the instant claim scope weighed against the specification support for said scope, the previous examiner’s supplemental Office action after RCE, and applicant’s last full substantive response (10/6/25) thereto. The examiner and AR discussed at length that the last response appeared to identify that a ‘triad’ of – but not one or more conjugates (aka not 1 or more tripeptides) thereof – the three (3) individual amino acids claimed (Trp, Tyr, and Phe (Y,W,F) and various ratios thereof) was that tested and quantified in the test data. Applicant indicated all of that discussed would be further weighed with overseas counsel in Israel. While no final agreement was reached, the examiner indicated he was open to further interview to advance prosecution on the merits.
Claims 46-48, 50-52, 54-57 and 66-81 remain pending and examined on the merits with claims 52 and 54-57 withdrawn fom consideration as not directed to the elected group by restriction requirement (maintained as final here).
Election/Restrictions
Claims 52 and 54-57 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/02/2024.
Specie Election
Applicant elected the specie of tyrosine, phenylalanine and tryptophan without traverse in the reply filed on 01/02/2024.
35 U.S.C. 112(b) - Maintained
(b) CONCLUSION.-The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 46-48, 50-51, and 66-81 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims are directed to "an effective amount of:".
The effective amount is contemplated in the specification on bridging pages 50- 51 as follows.
"The term "effective amount" relates to the amount of an active agent present in a composition, specifically, the mTOR agonist of the invention as described herein that is needed to provide a desired level of active agent in the bloodstream or at the site of action in an individual (e.g., the specific site of the tumor) to be treated to give an anticipated physiological response when such composition is administered. The precise amount will depend upon numerous factors, e.g., the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, intended patient use (i.e., the number of doses administered per day), patient considerations, and the like, and can readily be determined by one skilled in the art, based upon the information provided herein" (p. 50).
The specification exemplifies mM amounts of 0.01 to 30 (page 52).
The specification exemplifies unit dosage forms of 0.001 grams to about 100 grams (page 52).
The specification explains "an effective amount in accordance with the m TOR agonists of the present disclosure, specifically mTOR agonist comprising the at least two aromatic amino acid residues may be presented in any amount effective for selective and specific agonistic activity for mTOR mediated activities, specifically, in modulating proteasome dynamics in a cell" (page 51). Herein a plural amount of cells is not required.
The specification does not define an effective amount of (a), (b) and (c) and does not define to what is being effected and to what extent. Exemplifications are just that and are not considered definitions.
With compact prosecution in mind, the effective amount is being interpreted as any amount.
Response to Amendments/Arguments
Applicant’s amendments and arguments have been fully considered but not found persuasive for the reasons of record. Effective amount is not commensurate in scope with that described and cannot be ascertained in the context of the end results (scope claimed).
Claim Interpretations – Previously Noted
The preamble "A mammalian target of rapamycin (mTOR) agonist" is interpreted to be an intended use. The MPEP 2111.02 (II) states "If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction".
Moreover, upon meeting the limitations of the claims, the preamble is therefore also met. For example, a disclosure of the three amino acids would necessarily meet the preamble of a "A mammalian target of rapamycin (mTOR) agonist consisting of".
Consisting of is being interpreted as instructed by the MPEP 2111.03. "The transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. In re Gray, 53 F.2d 520, 11 USPQ 255 (CCPA 1931); Ex parte Davis, 80 USPQ 448, 450 (Bd. App. 1948) ("consisting of" defined as "closing the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith”).
Unit dosage form and unit dose are interchangeable. See specification page 48. A very broad exemplification is as followed. Unit dosage form and unit dose "and the like refer to both, solid dosage forms as known in the art, or to a liquid dosage form. The dosage forms are intended for peroral use, i.e., to be swallowed (ingested), or even injected or applicated in any other means, either by a subject in need thereof, or for administration by a medical practitioner" (current specification page 48).
This definition allows for the unit dosage form and unit dose to equate to a solid or liquid containing the claimed three amino acids. There is nothing to stop the reader from interpreting the above unit dosage form and unit dose as a powder form that can at once be taken orally. Capsule forms are examples and not a definition. Therefore, no real structure is imparted by the use of dosage units, dosage forms or the like.
The proviso of claim 46 is interpreted as a selection of at least one of (I) and combinations thereof or (II) and combinations thereof. More precisely (I) or (II) alone or (I) and (II) together. Art disclosing YWF will satisfy the proviso.
Claim 51 has the language of a first through third unit dosage consisting of an effective amount. This language does not impart any structural difference to the (a)-(c) limitations of claim 46.
The kit of claim 51 is not defined in the original disclosure. Therefore the limitation of the kit is met when the composition/compound of claim 51 is met. Limitations of (a), (b) and (c) are being interpreted as one molecule or separate molecules of "Tyr, Trp and/or Phe", "Y, Wand/or F", or YWF.
Claim Rejections - 35 USC § 102 - Maintained
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless -
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 46-47, 51, 66-67, 73 and 80 is/are rejected under 35 U.S.C. 102(a)(1)
as being anticipated by Peng et al. (CN101747410, Published 06-2010. A machine
translation is attached).
Peng et al. disclose a 308 mg amount of Phe-Tyr-Trp (Example 4, page 4 of 9). Example 4 Preparation of Phe-Tyr-Trp (FYW)
1) Preparation of Boc-Phe-Tyr-Trp-OBzl
Following the procedure to prepare Boc-Ala-Tyr-Trp-OBzl, 580 mg (47%) of the title compound was obtained as a colorless solid. ESI + -MS (m / e) 727 [M + Na] +. 2) Preparation of Phe-Tyr-Trp
Following the procedure for preparing Ala-Tyr-Trp, 308 mg (69%) of the title compound was obtained as a colorless powder. Mp: 148-149C; [a] D25 = 1.3 (c = 1.08, CH3OH); ESI + -MS (m / e) 514.9 [M + H] +; 1HNMR (BHSC-500Hz, DMSO-d6), 12.68 (s, 1H), 10.93 (s, 1H), 9.25 (s, 1H), 8.83 (d, J = 8Hz, 1H), 8.81 (d, J = 7.5Hz, 1H), 8.11 (s, 2H), 7.57 (d, J = 7.5Hz, 1H), 7.36 (d, J = 7.5Hz, 1H), 7.21 (m, 8H), 7.08 (d, J = 8.4Hz, 2H), 6.65 (d, J = 8.4Hz, 2H), 4.55 (m, 2H), 4.00 (s, 1H), 3.35 (d, J = 7Hz, 2H), 3.15 (m, 4H). 4) Preparation of Ala-Tyr-Trp .ocr_line, .ocr_header { display:block; }
Application/Control Number: 18/004,821
Page 10
Art Unit: 1692
Boc-Ala-Tyr-Trp-OBzl (500 mg) was dissolved in methanol, 15% Pd / C was added, hydrogen was passed for 48 hours, palladium on carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was added with 5 ml of 4N HCI / EtOAc, stirred at 0 C for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with anhydrous ether (30 ml X 3). This gave 240 mg (79%) of the title compound as a colorless powder. Mp.122-123C; [a] D25 = 16.6 (c = 1.23, CH3OH), ESI + -MS (m / e) 439 [M + H] +; 1HNMR (BHSC- 300Hz, DMSO-d6), 10.82 (s, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.08 (d, J = 7.5Hz, 1H), 7.58 (d, J = 7.5Hz, 1H), 7.31 (d, J = 7.5Hz, 1H), 6.98 (m, 5H), 6.64 (d, J = 8.4, 2H), 3.55 (q, J = 6.9Hz, J = 14.1Hz, 1H), 3.10 (m, 4H), 2.09 (s, 1H) 1.20 (d, J = 7.5 Hz, 3H).
Concerning the claimed unit dosage form consisting of an effective amount or any other recitation of unit, dosage, and/or dose and/or effective amount, this phraseology as interpreted above, is broadly exemplified in the original disclosure and not defined. The 308 mg of FYW is the claimed unit, dosage, and/or dose and/or effective amount.
This anticipates the claims.
Claim(s) 46-48, 50-51, 66, 69-70, 73, 75-76 and 78-81 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xin et al. (Oligotyrosines Inhibit Amyloid Formation of Human Islet Amyloid Polypeptide in a Tyrosine-Number-Dependent Manner, ACS Biomater. Sci. Eng., 5, pp. 1092-1099, Published 2019).
Xin et al. disclose 1.6mM solutions of tripeptide tyrosine (Tyr3) and hexapeptide tyrosine (Tyr6) in deionized water (p. 1093, upper right column). (claimed composition with pharmaceutically acceptable diluent). The 1.6mM solutions of Tyr3 and Tyr6 are the claimed mTOR in injectable unit dosage form and unit dosage having the effective amount of (a), (b) and (c) as YYY and YYYYYY.
Response to Amendments/Arguments
Applicant's amendments and arguments have been fully considered but they are not persuasive. The claim scope, per applicant’s own arguments, are drawn to a ‘triad’ of three (3) known amino acids (YWF). Presently a composition thereof is not claimed, per se. Thus, any ‘effective amount’ thereof does not change that the product itself – a mix of three (3) individual amino acids claimed - are known. Even if a composition were claimed/assertedly claimed, the asserted ‘effective amounts’ claimed are no commensurate in scope with the asserted ‘end results’ now claimed as being capable of achievement thereby. Thus, the rejection is maintained for the reasons of record. Applicant may consider methods of use (the withdrawn subject matter) by divisional (rather than continuation), which the examiner is open to taking up.
Claim Rejections - 35 USC § 103 - Maintained
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.
Claim(s) 46-48, 50-51, 66-67, 69-71, 73 and 80-81 is/are rejected under 35 U.S.C. 103 as being unpatentable over Peng et al. (CN101747410, Published 06- 2010. A machine translation is attached).
Scope of the Prior Art
The disclosure of Peng et al. is in the above 102 rejection and is incorporated by reference. Further teachings are as follows.
Peng et al. teach "It is composed of an agent or an adjuvant, that is, after compounding an effective amount of the compound of the present invention with a pharmaceutically acceptable carrier or diluent, it is prepared into any suitable pharmaceutical composition according to the conventional preparation method in the art. The composition is generally suitable for oral administration and injection" (p. 2 of 9).
Ascertaining the Difference
The disclosure of the 308 mg amount of Phe-Tyr-Trp is in a different location within Peng et al. than the teachings of an effective amount in Peng et al.
Obviousness
However, it would have been prima facie obvious for an ordinary artisan before the effective filing date of the claimed invention to have prepared a pharmaceutical composition generally suitable for oral administration or injection of the Phe-Tyr-Trp with at least a pharmaceutically acceptable carrier or diluent to prepare a unit dosage form consisting of effective amount of Phe-Tyr-Trp to cause one cell of the recipient/patient to undergo modulation of proteasome dynamics, (i) selective modulation of translocation and shuttling of proteasome, (ii) selective inhibition of translocation of proteasome from the nucleus to the cytoplasm, (iii) enhancement of recruitment of the proteasome into the nucleus, and/or (iv) retention, maintenance or enhancement of a nuclear or predominantly nuclear localization of proteasome.
The ordinary artisan would have done so with a reasonable expectation of success because Peng et al. teach "It is composed of an agent or an adjuvant, that is, after compounding an effective amount of the compound of the present invention with a pharmaceutically acceptable carrier or diluent (p. 2 of 9).
Claim(s) 46-48, 50-51, 66, 68-70, 72-73 and 80-81 is/are rejected under 35 U.S.C. 103 as being unpatentable over '074 (USPGPub 2007/0088074, Published 04-2007).
Scope of the Prior Art
Martynyuk et al. teach an article of manufacture useful in treating a neurological condition said article containing a pharmaceutical composition consisting essentially of at least one aromatic amino acid, isomer, or analog thereof, wherein said at least one aromatic acid, isomer or analog thereof is an admixture of ; or D-tyrosine, D- tryptophan, and D-phenylalanine (claim 2 of Martynyuk et al.). Due to claim 2 of Martynyuk et al. not requiring any additional substances in the pharmaceutical composition, the current "consisting of" limitation is met.
Martynyuk et al. teach the subject invention also provides an article of manufacture useful in treating a neurological condition characterized by overactivation of an ionotropic glutamatergic receptor. The article contains a pharmaceutical composition containing an AAA (L- and D-forms of phenylalanine, tyrosine, and tryptophan), and a pharmaceutically acceptable carrier or diluent (par. 57). The article of manufacture can be, for example, an intravenous bag, a syringe,... (See 074. Par. 59). This teaching reads on the limitations of an injectable formulated composition and a composition having a pharmaceutical acceptable carrier.
Martynyuk et al. teach the AAA can be administered as an isolated compound, it is preferred to administer the AAA in the form of a pharmaceutical composition (par. 57). The isolation of the AAA satisfies the unit dosage form, each unit dose in said unit dosage form consisting of an effective amount.
Concerning the effective amount, Martynyuk et al. teach According to the methods of the subject invention, an AAA is administered in an amount effective to increase the concentration of the AAA within the brain to a level above physiologically normal. For example, an AAA can be administered in an amount sufficient to bring the patient's AAA blood plasma level within the range of about 200 uM to about 2000uM (par. 50).
"However, (Martynyuk et al. goes on to teach) the appropriate concentration of AAAs in the blood for neuroprotection can be adjusted, as the permeability of the blood- brain barrier can vary markedly with different disease states. In addition, the precise dosage will depend on a number of clinical factors, for example, the type of patient (e.g., human, non-human mammal, or other animal), age of the patient, and the condition under treatment and its severity. A person having ordinary skill in the art would readily be able to determine, without undue experimentation, the appropriate dosages required to achieve the appropriate levels" (Martynyuk et al., par. 50). This teaching allows for manipulation of the exemplified range of blood plasma level within the range of about 200 uM to about 2000uM.
Ascertaining the Difference
The above teachings of Martynyuk et al. are not in one central location and thus require the ordinary artisan to assemble the teachings of Martynyuk et al.
Obviousness
Thus it would have been prima facie obvious for an ordinary artisan before the effective filing date of the claimed invention to have combined the teachings of Martynyuk et al. to arrive at the current invention with a reasonable expectation of success.
For example, starting from claim 2 of Martynyuk et al., the ordinary artisan would have chosen the pharmecutical triad composition of D-tyrosine, D-tryptophan, and D- phenylalanine from the limited options. Next adding a pharmaceutically acceptable carrier of diluent would have been obvious due to the teachings of Martynyuk et al. (par. 57). Concerning the effective amount, the ordinary artisan being instructed broadly by Martynyuk et al. to formulate an effective amount in paragraph 59, would have done so with an expectation of success.
Claim(s) 46-48, 50-51, 66-67, 69-71, 73-74, 77 and 80-81 is/are rejected under
35 U.S.C. 103 as being unpatentable over Liotta et al. (Novel antibiotics: second
generation macrocyclic peptides designed to trap Holliday Junctions,Tetrahedron Letters, 45, pp. 8447-8450, Published 2004) and Wu et al. (USPGPub20230025834, Foreign Priority application PCT/CN2019/078189 filed 03-2019).
Scope of the Prior Art
Liotta et al. teach the immediate below cyclic bistriad FWYFWY peptide (p. 8448- 8449).
Liotta et al. teach the cyclic FWYFWY peptide having antimicrobial properties and may be viable leads for a new class of antibiotics (p. 8447, right column and bridging pages 8449-8450).
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Ascertaining the Difference
Liotta et al. does not teach the above cyclic FWYFWY peptide in an unit dosage form of an effective amount with at least one pharmaceutically acceptable carrier/s, excipient/s, auxiliaries, and/or diluent/s.
Secondary Reference
Wu et al. teach cyclic peptide antibiotics (par. 2 of foreign application). Wu et al. teach administering a therapeutically effective amount of the cyclic peptide (par. 110 of foreign application) with a pharmaceutically acceptable excipient (par. 98 of foreign application) to treat a bacterial infection in a patient (par. 163, par 110 in ). Wu et al. teach oral and injectable dosage and preparations respectively (par. 93-94).
Obviousness
It would have been prima facie obvious for an ordinary artisan before the effective filing date of the claimed invention to have combined the cyclic FWYFWY peptide taught by Liotta et al. with a pharmaceutically acceptable carrier taught by Wu et al. The ordinary artisan would have done so to administer the cyclic FWYFWY peptide taught by Liotta et al. to a patient in need of a treatment for a bacterial infection. The ordinary artisan would have had a reasonable expectation of success in doing so because Liotta et al. teach the cyclic FWYFWY peptide having antimicrobial properties and may be viable leads for a new class of antibiotics.
Concerning the effective amount and unit dose (see Wu et al. par. 110), the ordinary artisan would have arrived at this amount via routine experimentation. MPEP 2144.05 II. A. and B. "[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).
Response to Amendments/Arguments (103)
Applicant's amendments and arguments have been fully considered but they are not persuasive. The claim scope, per applicant’s own arguments, are drawn to a ‘triad’ of three (3) known amino acids (YWF). Presently a composition thereof is not claimed, per se. Thus, any ‘effective amount’ thereof does not change that the product itself – a mix of three (3) individual amino acids claimed - are known. Even if a composition were claimed, the asserted ‘effective amounts’ claimed are no commensurate in scope with the asserted ‘end results’ now claimed as being capable of achievement thereby. Thus, the rejection is maintained for the reasons of record. Applicant may consider methods of use (the withdrawn subject matter) by divisional (rather than continuation), which the examiner is open to taking up.
The previous examiners previous response to arguments are retained for the record:
Applicant argues reference '074 (Martynyuk et al.) is administering repeated amounts of the current amino acids that cause concentrations of the amino acids to exceed desired concentrations in a purported patient. See page 22 of arguments.
"This results in approximately 48 doses per day. Accordingly, the estimated daily dose for human subjects (having an average weight of about 70Kg), would be: 14.5-gram X 48 doscs a day= 695.65 gram of tyrosine per day".
Note: Martynyuk et al. teach a much broader range than the range cited by applicant. See Martynyuk et al. paragraph 50.
Contrary to applicant's argument, the ordinary artisan practicing the disclosure of Martynyuk et al. would have reached the effective amount at some point before administering all 48 doses.
Additionally, applicant has not supplied evidence that one or more of the 48 doses by Martynyuk et al. would not cause a single cell of the recipient to undergo the modulation described in the disclosure.
Concerning the effective amount as argued by the applicant as being at much lower ranges, presumably than the ranges of Martynyuk et al., these "ranges" in Martynyuk et al. are blood concentrations. The claims are not directed to concentrations of the claimed m TOR's in blood but rather effective amounts.
Concerning applicant's arguments centered around Martynyuk et al. teaching the efficacy of the individual amino acids on pages 41-42, see claim 2 of Martynyuk et al. wherein the triad is claimed.
Concerning the synergistic property of the triad leading to the modulation on page 42 of applicant's arguments, the claims are not commensurate with the purported synergistic amount of the triad. Additionally, anticipation of the claims cannot be overcome by a showing of an unexpected result. The art discloses the triad, the claims do not explicitly or implicitly require an actual number of moles of the triad just an ambiguous amount (effective amount) of the triad.
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 MAURY AUDET whose telephone number is (571)272-0960. The examiner can normally be reached on M-Th. 7AM-5:30PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/MAURY A AUDET/Primary Examiner, Art Unit 1654
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