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, 18-23, and 28 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.
The term “premature hydrolysis” in claim 1 is a relative term which renders the claim indefinite. The term “premature” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 18-23, and 28 are also rejected because they depend either directly or indirectly from claim 1 and do not resolve the issues with respect to claim 1.
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.
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, 18-20, and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Calabresi et al. (US20020049200, from IDS), and further in view of RU228438 (from IDS), WO01/95876, Veronese et al. (DDT, 2005, 10(21), 1451-1458), and Yokoyama et al. (Pediatrics, 1999, 103(5), e67).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1, 18, 28, Calabresi teaches that taurultam has activity against neuroblastoma and other cancers including bladder cancer and that the dosage ranges are typically from 0.1-150 mg/kg, which reads on the claimed range of taurultam of 5 mg/kg to 280 mg/kg, and the claimed 5 mg/kg to 40 mg/kg and wherein the dosage amounts can be determined by one of ordinary skill in the art (a physician) in amounts sufficient to induce apoptosis in cancer cells ([0043-0044]; [0046]; [0057]; [0015-0017]; claims).
Regarding claim 19-20, Calabresi teaches wherein their taurultam can be administered/is administered in conjunction with an oncolytic agent or radiotherapy and wherein the compositions is delivered to the patient using parenteral/intravenous delivery and can be administered once daily for instance ([0015]; [0039]; [0043-0044]; [0057]; [0087]; claims).
Ascertainment of the difference between prior art and the claims
(MPEP 2141.02)
Regarding claims 1, 18-20, 28, Calabresi does not teach wherein their method of treating neuroblastoma comprises administering taurinamide and methylene glycol in addition to the taurultam in the claimed ratios or wherein at least one of the active agents is pegylated to delay premature hydrolysis. However, these deficiencies in Calabresi are addressed by RU228438, WO01/95876, Veronese.
RU2282438 teaches that it was known to use methylene glycol to treat bladder cancer in animals in amounts of 0.1-1 wt% (See abstract; Example 1, introduction of a 0.25% methylene glycol solution; Claim).
WO01/95876 teaches that taurinamides and sulfonamides are known in the art to be antimicrobial ([0021]; [0048]; claims). Taurinamide, which is also known as 2-aminoethanesulfonamide, falls into both classes of compounds and is specifically a taurinamide, specifically the original/simplest taurinamide, which is known in the art as taurinamide and as such would have the same antimicrobial properties as other taurinamides ([0021]; [0048]; claims).
Veronese teaches that “pegylation” of small molecule drugs, e.g. doxorubicin, camptothecin, taxol, etc. was known in the art to improve the solubility, pharmacokinetics (absorption, distribution, metabolism (includes hydrolysis), and excretion of the drug) by allowing the drugs to have a prolonged residence in the body and decreased degradation by metabolic enzymes (e.g. thereby delaying hydrolysis of the drugs), and the targeting of these anticancer agents (See: abstract; small-drug pegylation section pg. 1456).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to have combined the taurultam, methylene glycol, and taurinamide in order to develop the claimed combination for treating neuroblastoma because taurultam is known to be active against neuroblastoma and methylene glycol is known to be effective against other cancers, specifically solid tumors, which would include bladder cancer and neuroblastoma, especially since there are rare instances of neuroblastoma happening in the bladder as taught by Yokoyama (background; Methods), and it is known to combine multiple agents for treating cancer in order to form more effective combinations for treating cancer. It also would have been obvious to add taurinamide to the combinations because taurinamide is a known antimicrobial and it can be used as antibiotic to keep down infections in the catheters/ports used to deliver chemotherapy to patients while they are receiving regular chemotherapy treatments.
It would have been obvious to optimize the dosages of taurultam, methylene glycol and taurinamide to fall within the claimed ranges and within the claimed ratios because Calabresi teaches wherein the dosage amounts are routinely determined by one of ordinary skill in the art (e.g. a physician). It would have been obvious to combine/add methylene glycol into formulation with taurultam because it was known to combine taurultam with other chemotherapeutic agents to treat various cancers including neuroblastoma and it would be obvious to add methylene glycol because it was known to be useful for treating cancers including other solid tumors and would be obvious to try in treating neuroblastoma because neuroblastoma can occur in the bladder as discussed above. 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).
It also would have been obvious to one of ordinary skill in the art to pegylate at least one of the taurultam, taurinamide, and/or methylene glycol as now claimed because it was known in the art pegylate drugs, including small molecule drugs such as taurultam, taurinamide, and methylene glycol in order to helps to improve the solubility, pharmacokinetics (absorption, distribution, metabolism (includes hydrolysis), and excretion of the drug) by allowing the drugs to have a prolonged residence in the body and decreased degradation by metabolic enzymes (e.g. thereby delaying hydrolysis of the drugs), and the targeting of these anticancer agents. Thus, one of ordinary skill in the art would be motivated to pegylate at least one of the claimed drug(s) in order to provide the claimed benefits because this is something that one of ordinary skill in the art routinely does to small molecule drugs to provide the claimed benefits and other benefits as taught by Veronese.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 18-20, 21-23, 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Calabresi et al. (US20020049200, from IDS), and further in view of RU228438 (from IDS), WO01/95876, Veronese et al. (DDT, 2005, 10(21), 1451-1458), and Yokoyama et al. (Pediatrics, 1999, 103(5), e67) as applied to claims 1, 18-20, and 28 above and further in view of Wohlfart et al., “Efficient Chemotherapy of Rat Glioblastoma using Doxorubicin-loaded PLGA Nanoparticles with Different Stabilizers”, PLoS ONE 6: el 9121 (2011) (herein, Wohlfart) (from IDS), Ma et al. (‘Nanoparticles for combination drug therapy’ ACS Nano, 2013, 7(77), 9518-9525, accessed as part of NIH public access author manuscript) (From IDS), DeCroes (“Development of PLA-PEG nanoparticles for the delivery of non-toxic drug in combination...” MS Thesis, Clemson, 2014, https://tigerprints.clemson.edu/cqi/viewcontent.cqi?article=3623&context=all theses) (from IDS).
Determination of the scope and content of the prior art
(MPEP 2141.01)
The combined reference together teach the method of claims 1, 18-20, 28 as discussed above and incorporated herein.
Ascertainment of the difference between prior art and the claims
(MPEP 2141.02)
Regarding claim 21, the combined references do not teach wherein the composition is included in a nanoparticle and wherein the nanoparticle is configured to delay hydrolysis of the composition until the nanoparticle reaches the site of a tumor.
Regarding claim 22, the combined references do not teach wherein the nanoparticle comprises a core of the composition and an exterior coating, wherein the exterior coating is configured to prevent exposure of the composition prior to arrival of the nanoparticle at the site of the tumor.
Regarding claim 23, the combined references do not teach wherein the exterior coating comprises an absorbable polymer or lipid which breaks down as the nanoparticle travels from the site of insertion to the site of the tumor.
These deficiencies in the combined references are addressed by Wohlfart, Ma, and DeCroes.
Wohlfart disclosed and was directed generally to chemotherapy of neural tumors (specifically glioblastoma) using nanoparticles loaded with antineoplastic agents. Wohlfart teaches therapeutic nanoparticles comprising at least one oncologic drug, specifically doxorubicin which reads on the instantly elected anti-neoplastic agents (See abstract), and Wohlfart teaches nanoparticles comprising doxorubicin which are coated with absorbable polymers specifically PLGA (I-lactide, glycolide), which reads on the coating created from combinations of copolymers and multimers derived from polymer structured from at least one from the group consisting of the elected polymer glycolide, etc. (see entire document; Materials and methods section; abstract; results section; introduction section). Wohlfart disclosed administering a therapeutic nanoparticle comprising a core of doxorubicin encapsulated by PLGA to rats by intravenous injection which reads on administering to a body which is systemically administered (See entire document; Materials and methods section; and Results section, pg. 3, paragraph 3). Wohlfart further disclosed that the therapy with doxorubicin-loaded nanoparticles was effective (Abstract; results section; materials and methods section).
Wohlfart teaches coating their doxorubicin nanoparticles with the same coatings that are instantly claimed/preferred specifically copolymers of L-lactide, glycolide, which are/read on the claimed absorbable polymers, and wherein the coating further comprises glycols, specifically poloxamers, because Wohlfart disclosed coating the nanoparticles in poloxamer 188 (At page 2, paragraphs 3 and 6). Thus, because these are the same types of coatings that are disclosed in instant spec. they obviously are configured to prevent premature exposure of the at least one oncologic drug and taurolidine to the body prior to delivery to the site of the neuroblastoma/cancer, and are configured to prevent the premature hydrolyzation of the composition all of which read on instant claims 21-23.
Ma teaches that it was known in the art to form blended nanoparticles comprising two chemically different active agents for treating cancer within the core of the nanoparticle. Ma teaches that it was known in the art to combine disparate drugs into a single nanoparticle for delivery to patients, specifically they teach combinations of docetaxel with Pt(IV) coordination complexes or combinations of hydrophobic drugs, such as camptothecin, with the antibody trastuzumab (anti-HER2), along with hydrophilic drug doxil into the core of a nanoparticle (See pg. 3, paragraphs 1-2; Abstract). Consequently, the claimed invention, when taken as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the teachings of the prior art are fairly suggestive of the claimed invention especially since it was already known in the art to combine disparate drugs for treating cancer into the same core of a nanoparticle in order to form blended nanoparticles which enable simultaneous drug release in precisely balanced ratios and rates and in selectively targeted tissues in cells (see Ma: Abstract; pg. 3, paragraphs 1-2; etc.).
DeCroes teaches that nanoparticles carry therapeutic agents throughout the body and protect them from degradation. Specifically, DeCroes teaches that by encapsulating cancer therapeutic agents the drug is not exposed to the body and therefore is not released until it reaches the target, e.g. a tumor, and that nanoparticles have a much higher therapeutic half-life (See pg. 17, bridging paragraph to pg. 18) for further targeted delivery of the nanoparticles to the tissue/tumor, peptides, antibodies, etc. can be attached to the nanoparticles to increase their uptake affinity, and this attachment would broadly include covalent bonding or embedding, to increase their uptake affinity (og. 18; Abstract; General introduction; Neuroblastoma general physiology section; pg. 11; pg. 14).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been obvious to place the claimed composition into the PLGA nanoparticles of doxorubicin either in combination with the doxorubicin or in place of the doxorubicin because it was known to use nanoparticles having the claimed properties and claimed external/exterior coatings which afford the same properties to the composition and nanoparticles that are instantly claimed for delivery of the cancer treatment agents to the site of the tumors since nanoparticles are known in the art to carry therapeutic agents throughout the body and protect them from degradation. Specifically, DeCroes teaches that by encapsulating cancer therapeutic agents the drug is not exposed to the body and therefore is not released until it reaches the target, e.g. a tumor, and that nanoparticles have a much higher therapeutic half-life. It also would be obvious that the combination of active in the claimed composition could be incorporated into nanoparticles because it was known to form blended nanoparticles comprising two chemically different active agents for treating cancer within the core of the nanoparticle. Thus, it would be obvious to form the claimed nanoparticles for use in the claimed composition when looking to the combination of the prior art for the reasons discussed above and herein.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments/Remarks
Applicants amendments to the specification and claims have overcome the objections to the specification and claims, and applicant’s amendments have also overcome the previous 112 (b) rejections. Applicant’s submission of a terminal disclaimer and its approval on 1/15/26 have overcome the previous double patenting rejection.
Applicants amendments to the claims have also prompted the new grounds of rejection presented herein. Applicants arguments insofar as they pertain to the new grounds of rejection are addressed herein.
Applicants argue that none of the prior art documents teach wherein at least one of taurultam, taurinamide, or methylene glycol is pegylated with polyethylene glycols as is now required by applicant’s claims. Applicants further argue that it would not be obvious to administer the taurultam, taurinamide and methylene glycol in the claimed weight ratios.
Applicants then argue that Darouiche teaches using taurinamides and sulfonamides as antimicrobial agent for coating medical devices not for treating cancer. The examiner first respectfully points out that the claimed method has an intended use/purpose of treating neuroblastoma. However, the method as claimed only requires the active steps of administering a composition comprising the claimed taurultam, taurinamide and methylene glycol in the claimed weight ratio to any patient of any type and it does not have to be administered in any specific amounts. They further argue that Darouiche does not teach that taurinamide is effective against any type of cancer. The examiner respectfully points out that nothing in the instant claims actually requires cancer to be treated or the patients to which the composition is being administered to have cancer as the claims are currently written. Further, nothing in the instant claims requires all three components to have activity against cancer. Two of the agents are known to be effective against cancers including neuroblastoma which can be found in the bladder and therefore be a type of bladder cancer. Thus, whether or not taurinamide is taught in the art to be effective against cancer it would be obvious to include in the composition being administered for the reasons discussed above because it is known to use antimicrobials in various drug formulations to reduce chances of infections in the catheters/ports used to deliver chemotherapy to patients while they are receiving regular chemotherapy treatments. Especially since applicants have not provided any data showing that this combination is unexpectedly better than the single treatments alone for treating neuroblastoma or any evidence that the instantly claimed combination would not be obvious for the reasons which are detailed above and incorporated herein.
Applicants then argue that their claims clarify that at least one of taurultam, taurinamide, and methylene glycol be pegylated with PEGs and that this is not a nanoparticle system configured to shield the composition as is taught by the later secondary references. The examiner respectfully disagrees with applicants narrow reading of the instant claims. Nothing in the instant claims requires that the pegylation actually be done directly to the taurinamide, taurultam or methylene glycol molecules the way the claim is currently written. You can also pegylate these drugs indirectly by incorporating them into a nanoparticle and pegylating the nanoparticle. However, pegylating the drugs directly as is taught by the prior art Veronese as discussed above still does not make the instant claims non-obvious over the new combination of references in the new 103 rejection presented above because it was known in the art to pegylate drugs in order to improve the solubility, pharmacokinetics (absorption, distribution, metabolism (includes hydrolysis), and excretion of the drug) by allowing the drugs to have a prolonged residence in the body and decreased degradation by metabolic enzymes (e.g. thereby delaying hydrolysis of the drugs), and the targeting of these anticancer agents (See Veronese: abstract; small-drug pegylation section pg. 1456). Thus, the instant claims are still obvious when taken in view of the combination of the prior art for the reasons which are discussed above and incorporated herein.
Applicants then argue that the other dependent claims are also not obvious in view of the prior art of record for the reasons discussed above with respect to the pegylation of at least one of the claimed taurinamide, taurultam, and methylene chloride. The examiner respectfully disagrees for the reasons discussed above which are incorporated herein.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Erin E Hirt whose telephone number is (571)270-1077. The examiner can normally be reached 10:30-7:30 ET M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sue X Liu can be reached at (571)-272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIN E HIRT/Primary Examiner, Art Unit 1616