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 .
Application Status
The preliminary amendment filed on 11/24/2023 is acknowledged. Claims 34-67 are currently pending and under consideration.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Portugal on 5/26/2021. It is noted, however, that applicant has not filed a certified copy of the Portugal application as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements filed on 7/15/2024 and 11/06/2025 are acknowledged and have been considered except where lined through.
Specification
The disclosure is objected to because of the following informalities: Numerous times within the specification there is a reference to “Error! Reference source not found” (see for example, page 3 of the specification as originally filed).
Appropriate correction is required.
The use of the term NUZYRA, which is a trade name or a mark used in commerce, has been noted in this application numerous times. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains numerous embedded hyperlinks and/or other form of browser-executable codes. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 56 is objected to because of the following informalities: Claim 56 recites the phrase “…wherein R6 can be a C1-C10 straight chain alkyl….”. It is suggested that applicants remove “can be” and replace it with the affirmative “is”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(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.
Claims 40-42, 44-45, 50-51, 56 and 60 are 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.
Regarding claims 40-42, 44-45, 50-51 and 60, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 56, claim 56 recites the limitation “comprising at least one of oxygen, nitrogen, sulfur or phosphorus atom….” following the definitions of R6. However, it is unclear whether all of the definitions of R6 comprise at least one oxygen, nitrogen, sulfur or phosphorus atom or whether this limitation only pertains to the heteroaryl group. For prior art purposes, it will be construed as pertaining to any of the variables which would encompass carbonyl compounds such as those suggested by Honeyman et al. (cited below) .
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.
Claim(s) 34-53, 56, 58-59 and 61-67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Honeyman et al. (Antimicrob Agents Chemother 2015; 59:7044-7053, IDS) in view of Paratek Pharmaceuticals (WO2004/091513A2, 2004-10-28) referred to herein as Paratek 1, Johnston and Warchol (US8946196B2, 2015-02-03) and Britton and Raston (Chem. Soc. Rev. 2017-46,1250).
Honeyman et al. teach the synthesis of aminomethylcyclines (depicted below) comprising the following steps:
1) Reacting minocycline (2) and N-hydroxymethyl-phthalimide,
2) followed by deprotection of the modified monocyline with an amine (MeNH2) to form 9-aminomethylminocycline,
3) reacting the 9-aminomethylminocycline of step 2 with an aldehyde in the presence of NaCNBH3 (reducing agent to yield derivatives 7-10, 12-15, 23, 27, 28, 30-32 and 34-36, OR
4) reacting the 9-aminomethylminocycline of step 2 with an alkylating agent in the presence of a triethylamine (TEA, a proton acceptor) to generate compounds 16-18 and 19-20. (See Fig 2)
PNG
media_image1.png
618
1846
media_image1.png
Greyscale
Specifically, Honeyman et al. teach the synthesis of compound 28 which corresponds to omadacycline (Table 2 and Table 3). Note: The synthetic sequence does not depict a hydrogenation reaction during step 2, so it is assumed that such reaction was in the absence of hydrogenation. Moreover, omadacycline (cmpd 28) is produced using the reductive alkylation of the amine using an aldehyde so it would appear that the pivaldehyde was used as the aldehyde.
Honeyman et al. do not specifically teach the reaction conditions of each of the steps or that the process is operated as a semi continuous or continuous flow process.
Paratek 1 teaches the synthesis of 9-aminomethyl minocycline and derivatives thereof. Specifically, Paratek 1 teaches the following synthesis:
Reacting minocycline in trifluoroacetic acid and N-hydroxymethylphthalimide in HCl for 5-6 hrs at 40-50oC to generate 2,9-bis-aminomethylphthalimidominocycline.
Suspending 2,9-bis-aminomethylphthalimidominocycline in methylamine in methanol (10eq) at room temperature for 2-3 hours to generate 2,9-bis aminomethylminocycline, and
Adding 2,9-bis aminomethylminocycline to water/methanol and adjusting the pH to 3 by the addition of trifluoroacetic acid, followed by heating to 40oC for 1-2 hrs to obtain 9-aminomethylminocycline (page 31, Example 1).
Moreover, Paratek 1 teach making the benzyl derivative wherein the aldehyde is benzaldehyde. (Example 1). Lastly, Paratek 1 teach that the minocycline compounds that are basic in nature are capable of forming a wide variety of salts include, but not limited to a tosylate salt, wherein an acid addition salt of the base compounds are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or organic solvent (page 27, lines 18-37).
Johnston and Warchol teach the synthesis of 9-Alkyl Aminomethyl Minocycline derivatives, wherein the synthesis contains the following steps:
Minocycline hydrochloride (compound 2) was dissolved in methylsulfonic acid or hydrofluoric acid with methylsulfonic anhydride. N-hydroxymethyl phthalimide was added to the reaction mixture. The mixture was stirred at 20-35oC until the reaction was complete.
Suspending the product of step 1 in the EtOH. Aminolysis was carried out by using methylamine..
Compound 4 as freebase was transferred to a hydrogenation vessel which was charged with methanol and aldehyde. An inactivated Pd/C catalyst was charged and the vessel was pressurized with hydrogen gas. The reaction mixture was hydrogenated under hydrogen pressure around 30 Psi for about 24 hours. When conversion of compound 4 to 1 was complete, the solution was filtered and washed through a Celite pad. At this point the reaction mixture contained very low β C-4 epimer, around 3-7% (Example 1, scheme 1, depicted below).
Moreover, Johnston and Warchol teach that the compounds further comprises their pharmaceutically acceptable salts including, but not limited the tosylate salts, wherein the salts can be prepared in situ during the final isolation and purification of the compounds (Column 18, line60 to Column 19, line 5).
PNG
media_image2.png
908
418
media_image2.png
Greyscale
Britton and Raston reviews the advancement of multi-step continuous flow syntheses, while highlighting the rapid progress, benefits and diversification of this expanding field (Abstract). Moreover, Britton and Raston teach that at the core of continuous flow systems are pumps that drive fluids through channels, tubes or packed beds in a continuous fashion, wherein muti-step continuous flow platforms are essentially several reactions connected into a single flow sequence (page 1251, 1st column, 1st full paragraph). Of note, Britton and Raston teach that (1) continuous-flow synthesis aids multi-step transformations by providing efficient mixing and thermal control, (2) continuous-flow chemistry allows reaction and reagent confinement during multi-step transformations, (3) In-line purification of intermediate compounds is vital to increase reaction yields and efficiencies, (4) In-line spectroscopy allows detection of intermediate compounds to ensure maximal yields are maintained, and (5) Active Pharmaceutical Ingredients (APIs), natural products and commodity chemicals have benefited from continuous-flow syntheses (page 1250, Key learning points).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by Honeyman et al. so as to utilize in step 1 a solution of triflic acid methanesulfonic acid, ethanol in step 2, methanol within step 3, and produce a tosylate salt of the minocycline compound in view of the teachings of Paratek 1 and Johnston and Warchol. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Both Paratek 1 and Johnston and Warchol teach the reagents that can be used when utilizing the same starting material, intermediates and reactants.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the reaction time, temperature, excess reactants and pressure of the method taught by Honeyman et al. in view of the teachings of Paratek 1 and Johnston and Warchol. One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
Both Paratek 1 and Johnston and Warchol teach the general conditions used in the synthesis of 9-Alkyl Aminomethyl Minocycline derivatives.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP 2144.05.
Lastly, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by Honeyman et al. to a continuous flow syntheses in view of the teachings of Britton and Raston. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
Britton and Raston discuss the benefits of continuous flow syntheses.
Also see MPEP 2144.04: In reDilnot, 319 F.2d 188, 138 USPQ 248 (CCPA 1963) (Claim directed to a method of producing a cementitious structure wherein a stable air foam is introduced into a slurry of cementitious material differed from the prior art only in requiring the addition of the foam to be continuous. The court held the claimed continuous operation would have been obvious in light of the batch process of the prior art.).
Regarding claims 64-67, it is acknowledged that the prior art combination does not specifically teach the results of the purity or epimer content. However, it is recognized that the claimed limitations would necessarily be present by practicing the method suggested by the combination. It is noted that the Examples within the specification which describes the claimed process does not appear to characterize purity or epimer content. Only, conversion percent and yield.
Claim(s) 60 is/are rejected under 35 U.S.C. 103 as being unpatentable over Honeyman et al. (Antimicrob Agents Chemother 2015; 59:7044-7053, IDS) in view of Paratek Pharmaceuticals (WO2004/091513A2, 2004-10-28) referred to herein as Paratek 1, Johnston and Warchol (US8946196B2, 2015-02-03) and Britton and Raston (Chem. Soc. Rev. 2017-46,1250), as applied to claims 34-53, 56, 58-59 and 61-67, in further view of Cho and Kang (Tetrahedron 2005; 61:5725-5734).
The combination of Honeyman et al., Paratek 1, Johnston and Warchol and Britton and Raston has been described above and incorporated herein. In short, the combination teaches a syntheses of aminomethylcyclines (depicted below) comprising the following steps:
1) Reacting minocycline (2) and N-hydroxymethyl-phthalimide,
2) followed by deprotection of the modified monocyline with an amine (MeNH2) to form 9-aminomethylminocycline,
3) reacting the 9-aminomethylminocycline of step 2 with an aldehyde in the presence of NaCNBH
PNG
media_image3.png
86
622
media_image3.png
Greyscale
While the combination teaches the reductive amination utilizing NaCNBH3, the prior art does not teach that this step proceeded in the presence of an organic acid.
Cho and Kang teach direct and indirect reductive animation of aldehydes and ketones with solid acid-activated sodium borohydride (Title). Specifically, Cho and Kang teach while there are many effective reducing methods for these conversions such as NaBH3CN, most of these reagents have drawbacks (page 2725, 1st column, last few sentences). For example, Cho and Kang teach that cyanoborohydride is highly toxic and generate toxic by-products such as HCN, NaCN upon workup and may result in the contamination of the product with the toxic compounds (page 2725, 2nd column, sentence starting with Cyanoborohydride).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by the combination described above so as to utilize solid acid-activated sodium borohydride in view of the teachings of Cho and Kim. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Cho and Kang teach that cyanoborohydride is highly toxic and generate toxic by-products such as HCN, NaCN upon workup and may result in the contamination of the product with the toxic compounds.
Claim(s) 54-55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Honeyman et al. (Antimicrob Agents Chemother 2015; 59:7044-7053, IDS) in view of Paratek Pharmaceuticals (WO2004/091513A2, 2004-10-28) referred to herein as Paratek 1, Johnston and Warchol (US8946196B2, 2015-02-03) and Britton and Raston (Chem. Soc. Rev. 2017-46,1250), as applied to claims 34-53, 56, 58-59 and 61-67, in further view of Ley et al. (J. Chem. Soc. Perkin Trans. 1; 1999:1251-1252).
The combination of Honeyman et al., Paratek 1, Johnston and Warchol and Britton and Raston has been described above and incorporated herein. In short, the combination teaches a syntheses of aminomethylcyclines (depicted below) comprising the following steps:
1) Reacting minocycline (2) and N-hydroxymethyl-phthalimide,
2) followed by deprotection of the modified monocyline with an amine (MeNH2) to form 9-aminomethylminocycline,
3) reacting the 9-aminomethylminocycline of step 2 with an aldehyde in the presence of NaCNBH
PNG
media_image3.png
86
622
media_image3.png
Greyscale
While the combination teaches the reductive amination utilizing NaCNBH3, the prior art does not teach that this step proceeded with immobilized CNBH3 (cyanoborohydride).
Ley et al. teach synthesis of the alkaloids (±)-oxomaritidine and (±)-epimaritidine using an orchestrated multi-stop sequence of polymer supported reagents (Title). Specifically, Ley et al. teach the step of reacting an aldehyde with a primary amine under reductive amination conditions to generate a norbelladine derivative in excellent yield, any by-product or unreacted material, in this step being absorbed and easily washed off, wherein the reactions were performed using polymer supported cyanoborohydride (page 1251, 1st column, 2nd full paragraph).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by the combination described above so as to utilize polymer supported (immobilized) cyanoborohydride for the reductive amination in view of the teachings of Ley et al. . One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Ley et al. teach that the reductive amination using polymer supported cyanoborohydride proceeded quantitative conversion to the secondary amine.
Conclusion
Claims 34-56 and 58-67 are rejected.
Claim 57 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. In the instant case, the state of the art at the time the invention was made and current state of the art recognizes that reductive amination is the best approach to making a more substituted amine from a less substituted amine. In particular, making a more-substituted amine from a less-substituted amine through treatment with an alkyl halide often fails, because the product amine is more nucleophilic than the starting amine (see for example, James Ashenhurst (Alkylation of Amines (Sucks!), masterorganicchemistry.com/2017/05/26/amine-alkylation/, original 2017-05-26, updated 2025-07-03).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
BRANDON J. FETTEROLF, PHD
Primary Patent Examiner
Art Unit 1626
/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626