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 .
Response to Arguments
Applicant’s arguments, see Pages 1-3, filed 12/03/2025, with respect to the rejection(s) of claims 74-75, 78-82, 84-85, 87 and 90-93 under Tyler et al. (WO 2016025741 A1) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Tyler et al. (WO 2016025741 A1) and Rangaramanujam et al. (US Patent No. 20190142964).
The teachings of Tyler from the previous office action in view of the teachings of Rangaramanujam of hydroxyl-terminated PAMAM dendrimers covalently conjugated to a therapeutic agent via one or more linkages selected from the group consisting of disulfides, esters, ethers, thioesters, carbamates, carbonates, hydrazines, and amides, is obvious to claimed invention.
Applicant has overcome the 112b rejection by the cancelation of claim 83 and the nonstatutory double patenting rejection of claims 74-77, 79-80, 83-84 and 86-89 by a terminal disclaimer.
Applicant has canceled claim 83 and added claims 94-104. No new matter was added. Claims 74-82 and 84-104 is now evaluated on its merits.
Claim Rejections - 35 USC § 103
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.
Claims 74-82 and 84-104 are rejected under 35 U.S.C. 103 as being unpatentable over Tyler et al. (WO 2016025741 A1) in view of Rangaramanujam et al. (US Patent No. 20190142964) and Ghandehari et al. (WO 2012009406 A2).
Regarding claims 74-82 and 84-104, Tyler teaches methods for treating subjects with a proliferative disease of cancer of the brain, breast, colon, liver, renal, testicular and prostate comprising administering to the subject a composition comprising 4 or 6 (PAMAM) hydroxyl-terminated dendrimers (relevant to claim 98) covalently linked to or complexed with at least one therapeutic, prophylactic or diagnostic agent, in an amount effective to suppress or inhibit one or more symptom of the proliferative disease, or to image the proliferative disease, in the subject (relevant to claims 79-80 and 90-91) (claims 1, 3 and 27).
Tyler teaches the therapeutic agents of chemotherapeutic agent, immunotherapeutic agent, an anti-seizure agent, a steroid to decrease swelling, antibiotic, anti-antiogenic agent, and/or a diagnostic agent, and in particular BLZ-945 also known as sotuletinib (relevant to claims 75, 78, and 87) (para. 0016) in which the hydroxyl-terminated fourth generation PAMAM dendrimer (PAMAM-OH) is functionalized into clickable bifunctional dendrimer (intermediate 1) with 9 clickable groups on the surface using 2-(2- cyclooctyn-l-yloxy) acid (Figure 1 A). BLZ-945 is reacted with 2-azidoacetic acid to form azide-functionalized intermediate via an ester bond (Figure IB). The resulting azide on the 2-azidoacetyl linker is further reacted with the clickable groups of the bifunctional dendrimer to get dendrimer-BLZ-945 conjugate (Figure 1C)
PNG
media_image1.png
293
895
media_image1.png
Greyscale
(relevant to claim 84).
Tyler additionally teaches the dendrimer is linked to the therapeutic agent via a spacer ending in disulfide, ether, ester or amide bonds (relevant to claims 82 and 100) and the spacer can include polyethylene glycol having maleimide, succinimidyl and thiol terminations (relevant to claims 81, 85 and 99) (para. 0042).
In terms of claims 92-93, hepatocellular carcinoma is the most common type of liver cancer and enhancing tumor-specific cytotoxic T cell response is critical for treating liver cancer, in particularly hepatocellular carcinoma.
In terms of the receptor tyrosine kinase inhibitor at a concentration of between 5% and 20% by weight of the dendrimer conjugate, Tyler teaches approximately nine molecules of BLZ-945 conjugated to one molecule of the dendrimer (para. 0037). Taking in the molecular weight of 4 PAMAM at 14,214.17 and molecular weight of BLZ-945 at 398.48 x 9 one would get 25% of BLZ-945 to 4 PAMAM. When taking in to account the linker added to make up the dendrimer conjugate one would get 19% of BLZ-945 to dendrimer conjugate.
In terms of claims 94 and 101 wherein conjugation of the linker-receptor tyrosine kinase inhibitor occurs on less on less than 50% of the total available terminal hydroxyl groups of the dendrimer, Tyler teaches the above structure wherein 9 BLZ-945-linker is conjugated to 57 terminal hydroxyl groups thus having a percentage less than 50%.
Tyler fails to teach the method comprising therapeutic agents of sorafenib, sunitinib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, dasatinib, nintedanib, motesanib and wherein an ether bond is formed between the linker and a terminal hydroxyl group of the dendrimer.
Rangaramanujam teaches compositions of dendrimers of G1-10 PAMAM covalently conjugated to a therapeutic, and/or diagnostic agent via one or more linkages selected from the group consisting of disulfides, esters, ethers, thioesters, carbamates, carbonates, hydrazines, and amides to treat one or more diseases, conditions, and/or injuries of the eye, the brain and/or the central nervous system. The therapeutic, and/or diagnostic agent are encapsulated, associated, and/or conjugated in the dendrimer complex at a concentration of about 0.01% to about 30%, preferably about 1% to about 20%, more preferably about 5% to about 20% by weight (para. 0017-0018). In preferred embodiments, the spacer/linker is conjugated to the dendrimers via one or more of ether, thioester, carbamate, carbonate, hydrazine, or amide bonds for improved stability under physiological conditions, for example, compared to ester linkages (relevant to claim 74) (para. 0072). Rangaramanujam additionally teaches linkers of secondary amides which includes CONH (relevant to claim 86) (para. 0142).
Ghandehari teaches compositions for the treatment of cancers of breast tumor, neuroblastoma, testicular tumor, nervous system and the brain comprising an anti-cancer agent from a group which consist of dasatinib, sorafenib and sunitinib bonded to a macromolecule selected from a group which consist of dendrimers (relevant to claims 76-77, 88-89, 95-97 and 102-104).
Therefore, it would have been obvious to someone of ordinary skill in the art to have treated cancer by the composition of Tyler in which the therapeutic agent is dasatinib, sorafenib or sunitinib the linker is a secondary amide of CONH and the linker is conjugated to the dendrimer by an ether bond. One would have been motivated to do so from the teachings of Rangaramanujam of an ether bond between PAMAM dendrimers and linkers provides more stability compared to an ester bond wherein the linker can be CONH and the teachings of Ghandehari of anti-cancer agents of dasatinib, sorafenib and sunitinib being known to be connected to dendrimers. Thus the composition of Tyler would reasonably be substituted by the linker of CONH and form an ether bond for more stability as Rangaramanujam and Tyler teaches the same active ingredients to treat the same cancers, and substitute BLZ-945 with another well-known anti-cancer of dasatinib, sorafenib or sunitinib.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MIKHAIL O'DONNEL ROBINSON whose telephone number is (571)270-0777. The examiner can normally be reached Monday-Friday 7:30am-5:30pm.
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, Kortney Klinkel can be reached at 571-270-5239. 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.
MIKHAIL O'DONNEL. ROBINSON
Examiner
Art Unit 1627
/MIKHAIL O'DONNEL ROBINSON/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627