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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/05/2025 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The instant application claims domestic benefit of the provisional application, Application No. 63/212,297, filed on 6/18/2021.
Status of Claims/Application
Applicant’s amendment and remarks, dated 12/05/2025, is acknowledged.
Claim 1 has been amended. Claim 6 has been canceled. No new claims have been added.
Claims 1 – 5, and 7 are currently pending and are examined on the merits herein.
Information Disclosure Statement
Information disclosure statement (IDS) submitted by the applicant on 12/16/2025 is in compliance with the provisions of 37 CFR 1.97. It has been considered by the examiner.
Withdrawn Objections and Rejections
The objection to the informalities in the abstract of the specification is withdrawn with the submission of the amended abstract.
The rejection of claim 6 as being unpatentable over US 2015/0065446 A1 under 35 U.S.C. 103 is withdrawn in view of the cancellation of the claim.
The rejection of claims 1, 3, and 4 under 35 U.S.C. 103 as being unpatentable over US 2015/0065446 A1 is withdrawn in favor of the new grounds of rejection presented below. This rejection is withdrawn.
The rejection of claims 2, 5, and 7 under 35 U.S.C. 103 as being unpatentable over US 2015/0065446 A1, in view of Monslow et al. (2015) Hyaluronan – a functional and structural sweet spot in the tissue microenvironment. Front. Immunol. 6:231 is withdrawn in favor of the new grounds of rejection presented below. This rejection is withdrawn.
Claim Objections
The images of the structures listed in the claims 2 ,3, and 4 are blurry. Sharper and legible figures of the structures are necessary.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1- 5, and 7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification while being enabling for alleviating or inhibiting the progress of a tumor, does not reasonably provide enablement for preventing a tumor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instantly claimed invention encompasses a method for treating cancer by administering to a patient an effective amount of a hyaluronan conjugate, wherein the hyaluronan conjugate consists of one to four disaccharide units of D-glucuronic acid and N-acetylglucosamine, and one or more hydrogenated nimesulide, each covalently linked to the D-glucuronic acid of one of the disaccharide units and the cancer is breast cancer, lung cancer, or colorectal cancer.
The breadth of the claims
The scope of the amended claim 1 of the instant invention has been narrowed to the treatment of breast cancer, lung cancer, or colorectal cancer with the administration of the above mentioned hyaluronan conjugate.
The instant specification at paragraph [029] defines ‘The terms “treatment” and “treating” as used herein may refer to a preventative (e.g., prophylactic), curative or palliative measure. In particular, the term “treating” as used herein refers to the application or administration of the present hyaluronan conjugate or a pharmaceutical composition comprising the same to a subject, who has a medical condition, a symptom associated with the medical condition, a disease or disorder secondary to the medical condition, or a predisposition toward the medical condition, with the purpose to partially or completely alleviate, ameliorate, relieve, delay onset of, inhibit progression of, reduce severity of, and/or reduce incidence of one or more symptoms or features of said particular disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition, and/or to a subject who exhibits only early signs of a disease, disorder and/or condition, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder and/or condition.’
Thus, in its broadest reasonable interpretation, the treatment of a tumor indicates that the onset of the tumor, or symptoms thereof, has not yet occurred.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure describe the administration of the hyaluronan conjugate to MDA-MB-231 cells (human breast cancer cell line), A549 cells (human lung cancer cell line) and HT-29 cells (human colorectal cancer cell line) to access the tumor cell toxicity on various NIM-HA conjugates. The examples do not describe a study concerning the prevention of a tumor or a delayed onset of a tumor.
Additionally, the disclosure does not identify a method through which an ordinarily skilled artisan would be able to predictably determine that a subject or individual would have developed a tumor in order to determine that the claimed method resulted in prevention of the tumor.
The state of the prior art / the level of predictability in the art
Lewandowska, A.M., et al (2019) Environmental risk factors for cancer – review paper Ann. Agric. Environ. Med. 26(1); 1-7 teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2). Lewandowska teaches that physical, chemical and biological factors cause leukemia, liver, lung, and breast cancers; chemical and biological factors cause lymphoma, pancreatic, colorectal, stomach, esophageal, and cervical cancers; physical factors cause melanoma; chemical factors cause head or neck and brain tumors, and biological factors cause prostate and ovarian cancers.
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors were known that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that could contribute to the formation of cancer but are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause for an onset of several types of cancers and, therefore, suggest that there would be no method to predictably determine that any type of cancer was prevented using the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed in detail above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a subject or an individual would have predictably developed a tumor in order to apply the claimed method as a preventative measure. There is no known or disclosed method that could be used to establish that a tumor was prevented using the claimed method as there is no way to conclusively know that the subject would have developed a tumor without the claimed method. Therefore, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to develop a method that could be used to determine that a tumor was prevented.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Response to Arguments
Applicant's arguments filed 12/05/2025 regarding 35 U.S.C. 112(a) rejection because of the newly amended claim 1 have been fully considered but they are not persuasive. While applicant has narrowed down the scope of cancers that can be treated, the scope of “treating” as defined in the specification still encompasses “prevention” which is rejected for reasons indicated above.
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.
Claims 1 -5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0151336 A1, in view of Tavianatou A. G. et al (Hyaluronan: molecular size-dependent signaling and biological functions in inflammation and cancer, The FEBS Journal 286 (2019) 2883–2908), and Han W et al, (Preparation, characterization, and inhibition of hyaluronic acid oligosaccharides in triple-negative breast cancer, Biomolecules 2019, 9, 436).
US’336 teaches a compound conjugating a drug with a glycosaminoglycan, such as hyaluronic acid (HA), where the drug is useful for the treatment of diseases such as inflammation, auto-immune disease, allergy, infection and preferably cancer. The conjugated compound of US’336 can increase the concentration of drug at the specific site of disease by an interaction of the glycosaminoglycan used as target drug delivery carrier and the CD44 cell surface receptor, then enhancing the therapeutic efficacy and reducing the systemic side effect of the site-delivered drug (pg. 1, Abstract).
US’336 teaches that nimesulide is one of the widely used selective COX-2 antagonist which has superior gastrointestinal safety as compared to other non-steroidal anti-inflammatory drugs (NSAID). In recent time, nimesulide was supposed to act as an anti-cancer drug by inducing the expression of p21, a tumor suppressor gene, and inhibit the mammalian target of rapamycin (mTOR)-related pathway, an essential pathway for cell growth, cell proliferation, cell motility, cell survival, protein synthesis, of cancer cells (pg. 4, col. 1, [0056]).
US’336 teaches that the aim of the invention is binding or conjugating HA with a drug aforesaid, with or without a linker or spacer, by carboxyl group, hydroxyl group, or amino group of HA to accomplish working effect on specific location and specific time. Therefore, HA as a target delivery vehicle to carry the drug to the specific site that has abundant CD44 can produce better treatment efficacy and safety (pg. 4, col. 2, [0058]).
US’336 teaches that it provides a compound consisting of a conjugate from a glycosaminoglycan, preferably hyaluronic acid, and an active compound, wherein the active compound is conjugated by means of a functional group to a carboxylic group of the glycosaminoglycan, its derivative, or a salt thereof to form a covalent conjugation, and wherein the active compound is selected from a group consisting of Lenalidomide, Gemcitabine, and a COX-2 antagonist (pg. 4, col. 2, [0063]). The active compounds lenalidomide, Gemcitabine, or the preferred COX-2 antagonist Nimesulide or Celecoxib can be bound preferably directly by means the functional carboxylic group of the HA and the —NH2 group of the active compounds (pg. 5, col. 1, [0064]).
US’336 teaches that the preferred HA for conjugation has an average molecular weight in the range comprised from 10 kDa to 2000 kDa and the conjugation involves at least 40% of the carboxyl group of HA (pg. 5, col. 1, [0067]).
US’336 teaches anti-cancer drug conjugates of HA with Lenalidomide, HA with Gemcitabine, HA with Nimesulide, and HA with Celecoxib, where the Lenalidomide, Gemcitabine and Celecoxib are conjugated with HA by the formation of amide bond between the —NH2 group of Lenalidomide and the —COOH group of HA, respectively; furthermore, for the Nimesulide, the —NO2 group has been modified to —NH2 group so that the Nimesulide can covalently bind to —COOH group of HA via an amide bond to form the HA-NiNH2 conjugate (pg. 5, col. 1, [0069]). The structures of genuine Nimesulide (NiNO2) and the hydrogenation production, NiNH2, are shown in FIG. 5A, and the structure of HA-NiNH2 conjugate is shown in FIG. 5B. It is to be noted that the structure shown in FIG. 5B of US’336 is the same as the structure in claim 4 of the instant application.
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US’336 teaches that the antitumor efficacy of Lenalidomide and Nimesulide conjugated with HA when compared with Lenalidomide and Nimesulide alone showed significantly improved cytotoxicity effect and tumor suppression efficacy. The results aforementioned show that the US’336 shows a great contribution on enhancing the treatment effect of cancer drug including Lenalidomide and Nimesulide (pg. 5, col. 2, [0074]).
US’336 differs from the instantly claimed invention in that it does not explicitly teach short chain HA conjugates.
Tavianatou is a review about hyaluronan and the effects of its varying molecular weight, as high-molecular weight HA exhibits different biological properties than oligomers and low-molecular weight HA. The primary goal of the review is to critically present the importance of HA molecular size on cellular signaling, functional cell properties, and morphology in normal and pathological conditions, including inflammation and cancer. It states that a deeper understanding of these mechanisms could contribute to the development of novel therapeutic strategies (Abstract).
Tavianatou teaches that in oncology, o-HA (HA oligomers) and LMW HA (Low molecular weight HA ≤ 250 kDa) are suggested to be beneficial in many types of cancer as they can reduce cancer cell growth, migration, and invasion. Treatment of colon cancer cells with o-HA in cultures leads to a reduction in expression and activity of cyclooxygenase-2, followed by a decrease in HA synthesis. Moreover, o-HA inhibits tumor growth in vivo, and induces mammary and colon cancer cell apoptosis, as it triggers caspase-3 activity and suppresses the PI3K/Akt pathway which is responsible for cell survival (pg. 2893, col. 2, para. 3). o-HA is able to reduce HA accumulation in local tumors, preventing distant lung metastasis, the growth and invasiveness of malignant glioma cells, suppress the growth of B16F10 melanoma cells, and reduce the aggressiveness of ovarian carcinoma cells. HA fragments have been proven to sensitize cancer cells to chemotherapy. LMW HA regulates multidrug resistance of lymphoma cells and chronic myeloid leukemia cell lines to chemotherapy by reducing the activity of p-Akt and P-glycoprotein, leading to apoptosis. o-HA sensitizes malignant peripheral nerve sheath tumors to chemotherapy (pg. 2895, col. 1, para. 1).
Tavianatou provides a summary on HA molecular size-dependent effects in cancer in Table 2 (pg. 2894 – 95) in which o-HA consisting of 2 – 12 disaccharides and their function and role in various tumor types are listed.
Han describes the preparation of both odd- and even-numbered HA oligosaccharides (HAOs) with specific degrees of polymerization (DP) by different hydrochloric acid hydrolyses, and the characterization of their structures by means of HPLC, ESI-MS, and NMR. Biological evaluations indicated that all HAOs (DP3-11 and DP2-10) significantly inhibited the growth and migration of triple-negative breast cancer (TNBC) MDA-MB-231 cells. Among these oligosaccharides, the HA tetrasaccharide (DP4) was confirmed to be the minimum fragment necessary to inhibit MDA-MB-231 cells (Abstract).
Han teaches that their results have shown that the biological function is related to the size of HA fragments, and the inhibition of MDA-MB-231 grew nonlinearly as the size of the HAOs increased (Figure 7, pg. 10). The data in Figure 5 (pg. 9) show that all HAOs interacted with MDA-MB-231 cells. The DP2 and DP5 possessed weaker binding abilities than longer HAOs. More importantly, the molecular docking data in Figure 6 (pg. 10) suggest that the binding energies of HAOs with receptors are closely related to DP, which is in accordance with the results of HAO biological functions. The HA tetrasaccharide (HAO-DP4) was confirmed to be the minimum fragment necessary to inhibit TNBC. Han teaches that these similar results were also demonstrated in other GAG (glycosaminoglycan) oligosaccharides, for example, tetra oligosaccharide is the shortest heparan sulfate that binds to fibroblast growth factor 2 (FGF2). Han teaches that DP2 and DP3 may be too small to activate the receptors’ functions and the structure and order of sugar residues also play important roles for GAG biological functions. Han’s results suggest that the order of GlcA or GlcNAc was not the essential effect on the MDA-MB-231 of cell growth and that HAOs inhibited tumor growth (pg. 11, para. 2).
In summary, Han teaches the preparation and characterization of 10 different HAOs and their biological evaluation indicated that all HAOs significantly inhibited the growth and migration of TNBC MDA-MB-231 cells. Among the 10 oligosaccharides, DP4 was confirmed to be the minimum fragment necessary to inhibit MDA-MB-231 cells.
It would have been prima facie obvious to combine US’336 with Tavianatou and Han before the effective filing date of the claimed invention by shortening the HA chain of the nimesulide-HA conjugate disclosed in ‘336 to HA oligomers to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to make nimesulide drug conjugates of HA oligomers because Han teaches that all HA oligomers significantly inhibited the growth and migration of TNBC MDA-MB-231 cells. One of ordinary skill in the art would have a reasonable expectation of success because HA oligomers by themselves significantly inhibited the growth and migration of cancer cells, their further conjugation with the effective anti-cancer drug nimesulide would significantly increase the tumor suppression efficacy at the desired site of action in a patient in need of.
Response to Arguments
Applicant’s arguments filed 12/05/2025 explain that conjugates of US’446 have large HA polymers and that there is no example, synthesis, or test data involving conjugates of 1-4 disaccharide units (Remarks and Reponses, pg. 7, para. 2). The examiner agrees that the X is 1 and Y is 0, 1, 2, or 3 were never disclosed or exemplified in US’446 or US’336.
However, MPEP 2141(II)(C) states "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton."KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle."Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ."Id. at 418, 82 USPQ2d at 1396.
It would have been prima facie obvious for a person of ordinary skill in the art to look at the figure presented in the rejection above, and reproduced below and envisage shorter HA polymer chains conjugated with nimesulide as Han discussed above teaches the preparation of such short HA oligomers, and further teaches their biological role in inhibition and migration of cancer cells.
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Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 11,643,431 B2
Claims 1- 5, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 12 of U.S. Patent No. 11,643,431 in view of US 2017/0151336 A1.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1 -12 of the ‘431 patent recite the same compounds and structures of the instantly claimed invention. The ‘431 patent claims the use of these compounds for treating pulmonary infection.
The claims of the ‘431 patent differ from the instantly claimed invention in that the compounds are not used to treat cancer.
US’336 teaches a method of treating cancer by administering HA conjugated with an active compound. Nimesulide is a species of the claimed active compounds. US’336 teaches the structure of HA-Nim conjugate in FIG. 5B, which is presented in the claim 4 of the instantly claimed invention. US’336 teaches that the antitumor efficacy of Nimesulide conjugated with HA when compared with Nimesulide alone showed significantly improved cytotoxicity effect and tumor suppression efficacy.
It would have been obvious for one of ordinary skill in the art to modify the claims of the ‘431 patent with the teachings of US’336 to administer the compounds of the ‘431 patent to a patient suffering from cancer. It would have been prima facie obvious for one of ordinary skill in the art to modify the claims of the ‘431 patent to find a new effective use for the compounds because US’336 teaches that Nimesulide conjugated with HA showed improved cytotoxicity and tumor suppression efficacy, thus arriving at the instantly claimed invention.
This is a nonstatutory double patenting rejection.
US 12,281,133 B2
Claims 1- 5, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 4 of U.S. Patent No. 12,281,133 in view of US 2017/0151336 A1.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-4 of the ‘133 patent recite the same compounds and structures of the instantly claimed invention.
The ‘133 patent differs from the instantly claimed invention in that the administration of the compounds to treat cancer is not claimed.
US’336 teaches a method of treating cancer by administering HA conjugated with an active compound. Nimesulide is a species of the claimed active compounds. US’336 teaches the structure of HA-Nim conjugate in FIG. 5B, which is presented in the claim 4 of the instantly claimed invention. US’336 teaches that the antitumor efficacy of Nimesulide conjugated with HA when compared with Nimesulide alone showed significantly improved cytotoxicity effect and tumor suppression efficacy.
It would have been obvious for one of ordinary skill in the art to modify the claims of the ‘133 patent with the teachings of US’336 to administer the compounds of the ‘133 patent to a patient suffering from cancer. It would have been prima facie obvious for one of ordinary skill in the art to modify the claims of the ‘133 patent to find an effective use for the compounds because US’336 teaches that Nimesulide conjugated with HA showed improved cytotoxicity and tumor suppression efficacy, thus arriving at the instantly claimed invention.
This is a nonstatutory double patenting rejection.
US 12,285,441 B2
Claims 1- 5, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,285,441 in view of Tavianatou A. G. et al (Hyaluronan: molecular size-dependent signaling and biological functions in inflammation and cancer, The FEBS Journal 286 (2019) 2883–2908), and Han W et al, (Preparation, characterization, and inhibition of hyaluronic acid oligosaccharides in triple-negative breast cancer, Biomolecules 2019, 9, 436).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ‘441 patent is drawn to a method for treating breast cancer comprising a step of administering to a subject in need thereof a therapeutically effective amount of a conjugate of a hyaluronic acid and an active compound, wherein the active compound is nimesulide, and the hyaluronic acid has an average molecular weight comprised in the range from 350 kDa to 700 kDa.
The claims of the ‘441 patent differ from the instantly claimed invention in that the ‘441 patent does not teach short chain HA conjugates.
Tavianatou provides a summary on HA molecular size-dependent effects in cancer in Table 2 (pg. 2894 – 95) in which o-HA consisting of 2 – 12 disaccharides and their function and role in various tumor types are listed.
Han teaches the preparation and characterization of 10 different HAOs and their biological evaluation indicated that all HAOs significantly inhibited the growth and migration of TNBC MDA-MB-231 cells. Among the 10 oligosaccharides, DP4 was confirmed to be the minimum fragment necessary to inhibit MDA-MB-231 cells.
It would have been prima facie obvious to modify the claim of the ‘441 patent with the teachings of Tavianatou and Han before the effective filing date of the claimed invention by shortening the HA chain of the nimesulide-HA conjugate recited in the ‘441 patent to HA oligomers to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to make nimesulide drug conjugates of HA oligomers because Han teaches that all HA oligomers significantly inhibited the growth and migration of TNBC MDA-MB-231 cells. One of ordinary skill in the art would have a reasonable expectation of success because HA oligomers by themselves significantly inhibited the growth and migration of cancer cells, their further conjugation with the effective anti-cancer drug nimesulide would significantly increase the tumor suppression efficacy at the desired site of action in a patient in need of.
This is a nonstatutory double patenting rejection.
US 10,342,878 B2
Claims 1- 5, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 10,342,878 in view of Tavianatou A. G. et al (Hyaluronan: molecular size-dependent signaling and biological functions in inflammation and cancer, The FEBS Journal 286 (2019) 2883–2908), and Han W et al, (Preparation, characterization, and inhibition of hyaluronic acid oligosaccharides in triple-negative breast cancer, Biomolecules 2019, 9, 436).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1 and 2 of the ‘878 patent are drawn to a method for treatment of cancer comprising a step of administering a therapeutically effective amount of a compound consisting of a conjugate from a hyaluronic acid and an active compound, and the hyaluronic acid has an average molecular weight comprised in the range from 10 kDa to 2000 kDa. Nimesulide is a species recited in the genus of active compounds in the ‘878 patent and the method of treatment is directed to colon cancer or glioblastoma.
The claims of the ‘878 patent differ from the instantly claimed invention in that the ‘878 patent does not teach short chain HA conjugates.
Tavianatou provides a summary on HA molecular size-dependent effects in cancer in Table 2 (pg. 2894 – 95) in which o-HA consisting of 2 – 12 disaccharides and their function and role in various tumor types are listed.
Han teaches the preparation and characterization of 10 different HAOs and their biological evaluation indicated that all HAOs significantly inhibited the growth and migration of TNBC MDA-MB-231 cells. Among the 10 oligosaccharides, DP4 was confirmed to be the minimum fragment necessary to inhibit MDA-MB-231 cells.
It would have been prima facie obvious to modify the claim of the ‘878 patent with the teachings of Tavianatou and Han before the effective filing date of the claimed invention by shortening the HA chain of the nimesulide-HA conjugate recited in the ‘878 patent to HA oligomers to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to make nimesulide drug conjugates of HA oligomers because Han teaches that all HA oligomers significantly inhibited the growth and migration of TNBC MDA-MB-231 cells. One of ordinary skill in the art would have a reasonable expectation of success because HA oligomers by themselves significantly inhibited the growth and migration of cancer cells, their further conjugation with the effective anti-cancer drug nimesulide would significantly increase the tumor suppression efficacy at the desired site of action in a patient in need of.
This is a nonstatutory double patenting rejection.
US 9,572,832 B2
Claims 1- 5, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 5 of U.S. Patent No. 9,572,832 in view of Tavianatou A. G. et al (Hyaluronan: molecular size-dependent signaling and biological functions in inflammation and cancer, The FEBS Journal 286 (2019) 2883–2908), and Han W et al, (Preparation, characterization, and inhibition of hyaluronic acid oligosaccharides in triple-negative breast cancer, Biomolecules 2019, 9, 436).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1 - 5 of the ‘832 patent are drawn to a compound consisting of a conjugate from a hyaluronic acid and an active compound, and the hyaluronic acid has an average molecular weight comprised in the range from 10 kDa to 2000 kDa, for treating colon cancer, or glioblastoma. Nimesulide is a species recited in the genus of active compounds in the ‘832 patent.
The claims of the ‘832 patent differ from the instantly claimed invention in that the ‘832 patent does not teach short chain HA conjugates.
Tavianatou provides a summary on HA molecular size-dependent effects in cancer in Table 2 (pg. 2894 – 95) in which o-HA consisting of 2 – 12 disaccharides and their function and role in various tumor types are listed.
Han teaches the preparation and characterization of 10 different HAOs and their biological evaluation indicated that all HAOs significantly inhibited the growth and migration of TNBC MDA-MB-231 cells. Among the 10 oligosaccharides, DP4 was confirmed to be the minimum fragment necessary to inhibit MDA-MB-231 cells.
It would have been prima facie obvious to modify the claim of the ‘832 patent with the teachings of Tavianatou and Han before the effective filing date of the claimed invention by shortening the HA chain of the nimesulide-HA conjugate recited in the ‘832 patent to HA oligomers to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to make nimesulide drug conjugates of HA oligomers because Han teaches that all HA oligomers significantly inhibited the growth and migration of TNBC MDA-MB-231 cells. One of ordinary skill in the art would have a reasonable expectation of success because HA oligomers by themselves significantly inhibited the growth and migration of cancer cells, their further conjugation with the effective anti-cancer drug nimesulide would significantly increase the tumor suppression efficacy at the desired site of action in a patient in need of.
This is a nonstatutory double patenting rejection.
Claims 1 – 5, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 13 of Application No. 18/365,528.
Claims 1 – 5, and 7 of this application are patentably indistinct from claims 1- 13 of co-pending Application No. 18/365,528.
Claims 1 and 2 of the co-pending application recite a method for treating a locally advanced or metastatic solid or liquid tumor, comprising administering to a patient in need thereof an effective amount of a hyaluronan-nimesulide conjugate and an effective amount of fluoropyrimidine, wherein the solid tumor is a pancreatic tumor, colorectal tumor, liver tumor, melanoma, lung tumor, breast tumor, ovarian tumor, head or neck tumor, stomach tumor, prostate tumor, esophageal tumor, cervical or vaginal tumor, or brain tumor.
The claims 1 and 2 of the ‘528 application differ from the instantly claimed invention in that the ‘528 application includes an additional effective amount of fluoropyrimidine to be administered along with a therapeutically effective amount of a conjugate of a hyaluronic acid.
As both sets of claims recite a method of treatment of breast tumor, colorectal tumor or lung tumor by the administration of HA-nimesulide conjugate, even though they are not exactly matching, they are overlapping in scope. Thus rendering one set of claims to be unpatentable.
This is a nonstatutory double patenting rejection.
Response to Arguments
Applicant did not submit any arguments over the double-patenting rejections. MPEP states “A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional.”
The rejection is found to be proper, and is therefore maintained.
Conclusion
Claims 1 – 5, and 7 are rejected. No claims allowed.
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/JANAKI ANANTH MAHADEVAN/Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693