DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim 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 1-2, 6-8, 10, 19-20, 23, 26-27, 34, 36-37, 40-42, and 53 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 claim 1, the term “cleavable linker” renders the claim and dependent claims thereof indefinite as the term would have been insufficient to apprise one of ordinary skill in the art of the chemical structural element(s) required to provide for controlled release of the drug moiety. The instant claims read upon a dendrimer-drug conjugate comprising a ;plurality of first terminal groups (T1) comprising a cleavable linker the provides for controlled release of the drug moiety; however, one of ordinary skill in the art would not be apprised of the metes and bounds of a first terminal groups (T1) as the cleavable linker is only described in functional terms. The term “cleavable linker” is not sufficient to convey a chemical structure, chemical name or the like to the instantly claimed conjugate. There is nothing inherently wrong with defining some part of an invention in functional terms; however, a functional limitation must be evaluated and considered, just like any other limitation of the claim, for what it fairly conveys to a person of ordinary skill in the pertinent art in the context in which it is used. Functional descriptions of chemical compounds/compositions must be coupled with a known or disclosed correlation between function and structure. The deficiency is not remedied in claims 2, 6-8, 10, 19-20, 23, 26-27, 34, 36-37, 40-42, and 53.
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) 1-2, 6-8, 10, 13, 19-20, and 26-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Owen et al. WO 2020/014750 A1 (Owen); Gorzkiewicz, Michał, and Barbara Klajnert-Maculewicz. "Dendrimers as nanocarriers for nucleoside analogues." European Journal of Pharmaceutics and Biopharmaceutics 114 (2017): 43-56 (Gorzkiewicz); and Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel medicine and infectious disease. 2020 Mar 5;34:101615 (Al-Tawfiq) in combination.
Claims 1-2, 6-8, 10, 13, are 19-20 are drawn to a dendrimer-drug conjugate comprising:
i) a core unit (C); and
ii) building units (BU), each building unit being a lysine residue or an analogue thereof;
wherein the core unit is covalently attached to at least two building units via amide linkages, each amide linkage being formed between a nitrogen atom present in the core unit and the carbon atom of an acyl group present in a building unit; and
wherein the dendrimer-drug conjugate has from three to six generations of building units; and wherein building units of different generations are covalently attached to one another via amide linkages formed between a nitrogen atom present in one building unit and the carbon atom of an acyl group present in another building unit; the dendrimer-drug conjugate further comprising:
iii) a plurality of first terminal groups (T1) attached to an outer building unit of the dendrimer, comprising a drug moiety comprising a Remdesivir nucleoside and a cleavable linker that provides for controlled release of the drug moiety; and
iv) a plurality of second terminal groups (T2) attached to an outer building unit of the dendrimer, comprising a hydrophilic polymeric group; or a pharmaceutically acceptable salt thereof.
Claims 26-27 are drawn to a pharmaceutical composition comprising a plurality of dendrimer-drug conjugates or pharmaceutically acceptable salts thereof, wherein the dendrimer-drug conjugates are as defined in claim 1.
Owen generally relates to drug-dendrimer conjugates comprising a dendrimer including a core and building units, the outermost generation of building units including one or more pharmaceutically active agents attached via a cleavable linker group (page 1, lines 4-9). Owen also relates to pharmaceutical compositions and methods of treatment comprising the drug-dendrimer conjugates, and to processes and synthetic intermediates for producing the drug-dendrimer conjugates. Owen teaches that there is a need for alternative formulations and delivery means for delivering drugs to reduce side effects, improve dosage regimens and improved therapeutic window, which may lead to better compliance and efficacy of a drug for patients, while being stable, and practical to manufacture, and having a generally homogenous composition (page 2, lines 3-6).
Owen teaches a dendrimer comprising: i) a core unit (C); and ii) building units (BU), each building unit being a lysine residue or an analogue thereof; wherein the core unit is covalently attached to two building units via amide linkages, each amide linkage being formed between a nitrogen atom present in the core unit and the carbon atom of an acyl group present in a building unit; the dendrimer being a five generation building unit dendrimer; wherein building units of different generations are covalently attached to one another via amide linkages formed between a nitrogen atom present in one building unit and the carbon atom of an acyl group present in another building unit; the dendrimer further comprising: iii) a plurality of first terminal groups (T1) each comprising a cabazitaxel residue covalently attached to a diglycolyl linker group; and iv) a plurality of second terminal groups (T2) each comprising a PEG group; wherein at least one third of the nitrogen atoms present in outer building units are each covalently attached to a first terminal group; and at least one third of the nitrogen atoms present in outer building units are each covalently attached to a second terminal group; or a pharmaceutically acceptable salt thereof (page 2, lines 12-33).
Owen teaches that In some embodiments, the core is:
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(page 3).
In some embodiments, the building units are each:
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wherein the acyl group of each building unit provides a covalent attachment point for attachment to the core or to a previous generation building unit; and wherein each nitrogen atom provides a covalent attachment point for covalent attachment to a subsequent generation building unit, a first terminal group or a second terminal group.
Owen teaches that in some embodiments, the dendrimer has five complete generations of building units. In some embodiments, each first terminal group (T1) is:
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(page 3).
In some embodiments, the second terminal groups comprise PEG groups having an average molecular weight in the range of from 1000 to 2500 Daltons. Owen teaches that in some embodiments, the dendrimer comprises surface units comprising an outer building unit attached to a first terminal group and a second terminal group, the surface units having the structure:
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and wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of from about 1750 to 2500 Daltons (page 4). In some embodiments, the dendrimer has from 28 to 32 surface units, preferably from 30 to 32 surface units.
In some embodiments, the dendrimer is:
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in which T1' represents a first terminal group which is
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or T1' represents H, wherein less than 5 of T1' are H; and T2' represents a second terminal group which is
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wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of from about 1750 to 2500 Daltons, or T2' represents H, and wherein less than 5 of T2' are Н (pages 5-6).
Owen also provides pharmaceutical compositions, both for veterinary and for human medical use, which comprise the dendrimers of the disclosure or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients, stabilizers, or the like (page 31). The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. In some embodiments, the composition is a pharmaceutical composition, and wherein the composition comprises a pharmaceutically acceptable excipient.
Owen differs from the instantly claimed invention in that Owen does not teach a dendrimer-drug conjugate wherein the drug is Remdesivir; however, this deficiency would have been obvious in view of the teachings of Gorzkiewicz and Al-Tawfiq in combination.
In the instant case, the references may be combined to show obviousness because Owen, Gorzkiewicz, and Al-Tawfiq dendrimer-drug conjugates or Remdesivir. They are from the same field of endeavor, and/or are reasonably pertinent to a dendrimer-drug conjugate comprising a Remdesivir nucleoside.
Gorzkiewicz teaches that dendrimers were intensively studied for delivery of nucleoside analogues (NAs), essential elements of antiviral therapies, as well as treatments of leukemia, lymphoma and various types of solid tumors (Abstract). Gorzkiewicz summarized available data concerning the possibility of application of dendrimers as delivery devices for nucleoside analogues and their active, triphosphate forms. Gorzkiewicz teaches dendrimer-nucleoside analog conjugates (Table 3).
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Gorzkiewicz teaches scientific data on the use of dendrimers as drug delivery devices show that these macromolecules, usually after surface modification, can serve as effective nanocarriers of nucleoside analogues both in complexed and conjugated form (pages 53-54). Results suggest that such transport system hold potential to increase the efficiency and reduce the side effects of antiviral and anticancer therapy.
Al-Tawfiq teaches that it had been suggested that remdesivir might be an option for the therapy of patients with COVID-19. In a case report, remdesivir treatment was started intravenous on day 7 in a patient with COVID-19. Given the broad-spectrum anti-CoV activity of remdesivir that were demonstrated in pre-clinical studies; a randomized, controlled, double blind clinical trial is planned to evaluate the efficacy and safety of remdesivir in hospitalized patients with mild or moderate COVID-19 respiratory disease and this trial has already involved 308 hospitalized adult patients.
In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983).
It would have been obvious employ the dendrimer of Owen to deliver a therapeutically effective amount of Remdesivir to subject having COVID-19. One would have been motivated to do so in order to reduce side effects, improve dosage regimens and improved therapeutic window, which may lead to better compliance and efficacy of a drug for patients. One would have had a reasonable expectation of success as Gorzkiewicz teaches the use of dendrimers to deliver nucleoside analogs.
All of the instant limitations are taught by the combination of Owen, Gorzkiewicz, and Al-Tawfiq. A person of ordinary skill in the art would have had a reason to combine the teachings of Owen, Gorzkiewicz, and Al-Tawfiq. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Owen, Gorzkiewicz, and Al-Tawfiq. Thus, claims 1-2, 6-8, 10, 13, 19-20, and 26-27 would have been obvious based on the preponderance of the evidence.
Claim(s) 34, 36-37, 40-42, and 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Owen et al. WO 2020/014750 A1 (Owen); Gorzkiewicz, Michał, and Barbara Klajnert-Maculewicz. "Dendrimers as nanocarriers for nucleoside analogues." European Journal of Pharmaceutics and Biopharmaceutics 114 (2017): 43-56 (Gorzkiewicz); and Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel medicine and infectious disease. 2020 Mar 5;34:101615 (Al-Tawfiq) in combination as applied to claims 1-2, 6-8, 10, 13, 19-20, and 26-27 above.
Owen differs from the instantly claimed invention in that Owen does not teach a conjugate comprising Remdesivir and does not teach administration to an instant subject in need thereof; however, it would have been obvious to deliver Remdesivir to a subject in need of treatment for COVID 19 for the reasons set forth supra. Thus, claims 34, 36-37, 40-42, and 53 would have been obvious based on the preponderance of the evidence.
Conclusion
Claims 1-2, 6-8, 10, 13, 19-20, 23, 25-27, 34, 36-37, 40-42, and 53 are pending. Claims 1-2, 6-8, 10, 13, 19-20, 23, 26-27, 34, 36-37, 40-42, and 53 are rejected. Claim 25 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. No claims are allowed.
Contacts
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PATRICK T LEWIS whose telephone number is (571)272-0655. The examiner can normally be reached Monday to Friday, 10 AM to 4 PM EST (Maxi Flex).
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, Shaojia Jiang can be reached at (571) 272-0627. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PATRICK T LEWIS/Primary Examiner, Art Unit 1691
/PL/