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 .
Status of the Claims
Pursuant to the amendment dated 08/13/2025, claims 1-4 and 13-15 have been cancelled.
Claims 5-12 are pending and under current examination.
All rejections not reiterated have been withdrawn.
The statutory double patenting rejection over copending Application No. 17916645 has been withdrawn in view of the cancellation of instant claim 13 and the nonstatutory double patenting rejection over the same application has been withdrawn in view of the terminal disclaimer filed in the instant application on 08/13/2025.
A terminal disclaimer is on file for US Application No. 17315962.
Claim Objections
Claims 5-12 are objected to because of the following informalities: Each of claims 5-12 recite with a salt of tetrabutylammonium of HA. This language is awkward; the examiner recommends “with a tetrabutylammonium salt of HA”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5-12 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.
Claims 5-12 each recite the limitation "the nucleophilic substitution". There is insufficient antecedent basis for this limitation in the claim.
Each of claims 5-12 recite “is subsequently obtained”; however, the claim does not define what the obtaining is subsequent to, therefore the scope of the claim is unclear.
Claims depending from rejected claims have also been rejected because they incorporate all of the limitations of the claims from which they depend, but fail to resolve the indefiniteness concerns outlined above.
Nonstatutory 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 5-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 17917653 in view of Bassi et al. (Journal of Urology Vol 185, pp 445-449; publication year: 2011; cited in the IDS filed on 12/14/2023) and further in view of Nichols et al. (US 2005/0080075; publication date: 04/14/2005; cited in the IDS filed 12/14/2023).
Inter alia, the claims of the ‘653 application embrace a method of treating bladder cancer by administering a HA-paclitaxel conjugate. The HA-paclitaxel conjugate has a degree of derivatization of from 15-21% and the HA has a molecular weight of from 140,000 to 250,000 Da. The method of claim of forming the conjugate produces a HA-conjugate wherein an ester bond is formed between the carboxyl of the HA and the spacer/linker, which is in turn bound to by an ester bond through its carboxyl to the hydroxyl group at C2’ of paclitaxel via 4-bromobutyric acid. The conjugate is formulated in sterile isotonic solution of 5% glucose. The conjugate is formed by the method recited in the instant claims.
The claims of the ‘653 application do not recite limitations describing a treatment protocol as required by the instant claims.
Bassi discloses a method of treating bacillus Calmette-Guerin refractory carcinoma in situ (CIS) of the bladder by intravesical instillation of a paclitaxel-hyaluronic acid conjugate, wherein the paclitaxel is linked to the hyaluronic acid by a 4-bromobutyric acid linker (title; abstract; page 446, left col). The paclitaxel-HA conjugate is administered at a dose of 600 mg for 6 consecutive weeks (abstract; Table 2 on page 448).
It would have been prima facie obvious to follow the details of the dosing regimen disclosed by Bassi. The skilled Artisan would have been motivated to do so because this regimen showed efficacy against bacillus Calmette-Guerin refractory carcinoma in situ (CIS) of the bladder. The skilled Artisan would have had a reasonable expectation of success because this would merely require dosing the patients as described by Bassi.
It is noted that the dosing regimen disclosed by Bassi lasted 6 consecutive weeks; however, the dosing schedule recited in the instant claims is continued for 12 consecutive weeks.
Nichols, in the analogous art of cancer chemotherapeutics, discloses that standard clinical trials may be used to optimizing dose and dosing frequency for any particular compound (0183).
It would have been prima facie obvious for one having ordinary skill in the art to test several different dosing protocols in order to optimize efficacy of treatment. The skilled Artisan would have been motivated to do so in order to find the best treatment dose and schedule. See MPEP 2144.05(II)(A) and Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") Testing different dosing schedules is considered routine in the art, therefore the examiner does not consider the limitation requiring the paclitaxel-HA conjugate to be administered for 12 weeks to patentably define over the prior art absent unexpected results.
The instant claims recite the intended outcome that the patient at the end of the 12 consecutive weeks of treatment has a 75% probability to be negative for both endoscopic examination and bioptic analysis as the patient did not have any tumor cell detectable at bladder level after cytology of the mucosa and urothelium. As explained above, it would have been prima facie obvious to extend duration of treatment with the paclitaxel-HA conjugate for 12 weeks as part of the process of discovering the optimal treatment regimen. The probability of being negative for both endoscopic examination and bioptic analysis due to no detectable tumor cells at bladder level is an outcome that is derived from following obvious and routine steps to optimize treatment protocol. This outcome is a natural consequence of the combination of prior art elements and for this reason, the intended outcome does not patentably define over the cited prior art. See MPEP 2145(II): "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). See also MPEP 2112: Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination.
The instant claims require a step of adding a solution of HA salt with tetrabutylammonium to a paclitaxel intermediate. This step is taught in the method of making the paclitaxel-HA conjugate in claim 1 of the ‘653 application. This is a step in making the paclitaxel-HA used in the ‘653 invention.
This is a provisional nonstatutory double patenting rejection.
Claims 5-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-9 of copending Application No. 17916645 in view of Bassi et al. (Journal of Urology Vol 185, pp 445-449; publication year: 2011; cited in the IDS filed on 12/14/2023) and further in view of Nichols et al. (US 2005/0080075; publication date: 04/14/2005; cited in the IDS filed 12/14/2023).
Inter alia the claims of the ‘645 application are directed to a HA-paclitaxel conjugate wherein the conjugate has an ester bond between the carboxyl group of HA and a spacer, in turn bound by an ester bond through its carboxyl to the hydroxyl group of C2’ of paclitaxel, wherein the spacer is 4-bromobutyric acid and wherein the derivatization degree of paclitaxel in the HA-paclitaxel conjugate is between 15-21%. The conjugate is formulated in sterile, isotonic water containing 5% glucose. The conjugate is formed according to the method described in the Italian patent application IT 102018000009731, which is a family member of the instant application. Therefore the conjugate is formed by the method recited in the instant claims.
The claims of the ‘645 application do not recite the method steps for treating non-muscle invasive bladder cancer recited in the instant claims.
Bassi discloses a method of treating bacillus Calmette-Guerin refractory carcinoma in situ (CIS) of the bladder by intravesical instillation of a paclitaxel-hyaluronic acid conjugate, wherein the paclitaxel is linked to the hyaluronic acid by a 4-bromobutyric acid linker (title; abstract; page 446, left col). The paclitaxel-HA conjugate is administered at a dose of 600 mg for 6 consecutive weeks (abstract; Table 2 on page 448).
It would have been prima facie obvious to follow the details of the dosing regimen disclosed by Bassi. The skilled Artisan would have been motivated to do so because this regimen showed efficacy against bacillus Calmette-Guerin refractory carcinoma in situ (CIS) of the bladder. The skilled Artisan would have had a reasonable expectation of success because this would merely require dosing the patients as described by Bassi.
It is noted that the dosing regimen disclosed by Bassi lasted 6 consecutive weeks; however, the dosing schedule recited in the instant claims is continued for 12 consecutive weeks.
Nichols, in the analogous art of cancer chemotherapeutics, discloses that standard clinical trials may be used to optimizing dose and dosing frequency for any particular compound (0183).
It would have been prima facie obvious for one having ordinary skill in the art to test several different dosing protocols in order to optimize efficacy of treatment. The skilled Artisan would have been motivated to do so in order to find the best treatment dose and schedule. See MPEP 2144.05(II)(A) and Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") Testing different dosing schedules is considered routine in the art, therefore the examiner does not consider the limitation requiring the paclitaxel-HA conjugate to be administered for 12 weeks to patentably define over the prior art absent unexpected results.
The instant claims recite the intended outcome that the patient at the end of the 12 consecutive weeks of treatment has a 75% probability to be negative for both endoscopic examination and bioptic analysis as the patient did not have any tumor cell detectable at bladder level after cytology of the mucosa and urothelium. As explained above, it would have been prima facie obvious to extend duration of treatment with the paclitaxel-HA conjugate for 12 weeks as part of the process of discovering the optimal treatment regimen. The probability of being negative for both endoscopic examination and bioptic analysis due to no detectable tumor cells at bladder level is an outcome that is derived from following obvious and routine steps to optimize treatment protocol. This outcome is a natural consequence of the combination of prior art elements and for this reason, the intended outcome does not patentably define over the cited prior art. See MPEP 2145(II): "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). See also MPEP 2112: Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination.
The instant claims recite and product by process language to define the HA-paclitaxel prodrug. Product by process language does not further limit the claimed method of treating non-muscle invasive bladder cancer beyond the structure implied by the recited steps. According to MPEP 2113: product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.
This is a provisional nonstatutory double patenting rejection.
Claims 5, 6, 9, and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14, 17-24, 27, 28, and 30 of U.S. Patent No. 7,897,584 (cited in the IDS filed 12/14/2023) in view of Bassi et al. (Journal of Urology Vol 185, pp 445-449; publication year: 2011; cited in the IDS filed on 12/14/2023) and further in view of Nichols et al. (US 2005/0080075; publication date: 04/14/2005; cited in the IDS filed 12/14/2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims.
Inter alia the claims of the ‘584 patent embrace a method for treatment of tumors, including bladder tumors, which comprises administering to a subject in need for such treatment a therapeutically effective amount of taxane, specifically paclitaxel, covalently bonded to hyaluronic acid. The paclitaxel is covalently bonded to hyaluronic acid via a spacer that is 4-bromobutyric acid, i.e. a prodrug consisting of a conjugate of HA with paclitaxel, wherein the HA is indirectly bound to the paclitaxel through 4-bromobutyric acid. The conjugate is a component of a pharmaceutical composition having pharmaceutically acceptable excipients and diluents. The spacer is bound via an ester bond to a carboxylic group of hyaluronic acid with an esterification degree of 6.8-22% (i.e. wherein the HA has a degree of derivatization embracing the value(s) for this parameter required by the instant claims). The HA has a molecular weight of 39,000 to 200,000 Da, which overlaps with the range for this parameter required by the instant claims. See MPEP 2144.05. With regard to the limitation “and the 4-bromobutyric acid spacer in turn bound with an ester bond through its carboxyl group to the hydroxyl group of the carbon in C2’ of paclitaxel” recited in the instant claims, the examiner considers this prima facie obvious because the if the 4-bromobutyric acid spacer is bound via an ester bond to a carboxylic group of hyaluronic acid as required by the claims of the ‘584 patent, then the only functional group on the spacer left to react with the paclitaxel is the carboxyl group, and there are only a small number of reactive groups on the paclitaxel to choose from to form the link via the carboxyl group of 4-bromobutyric acid, including the C2’ hydroxyl. Thus, this linkage is obvious to try. The specification of the ‘584 patent indicate that the conjugate claimed therein has been formed by a step entailing contact with tetrabutylammonium in an anhydrous solvent (see col 13, lines 37-41). Thus, the conjugate inherently had been formed by a method falling within the scope of the claims.
The claims of the ‘584 patent do not mention treatment of NMIBC by intravesical instillation, do not identify a dose, and they do not recite a limitation on treatment schedule.
Bassi discloses a method of treating bacillus Calmette-Guerin refractory carcinoma in situ (CIS) of the bladder by intravesical instillation of a paclitaxel-hyaluronic acid conjugate, wherein the paclitaxel is linked to the hyaluronic acid by a 4-bromobutyric acid linker (title; abstract; page 446, left col). The paclitaxel-HA conjugate is administered at a dose of 600 mg for 6 consecutive weeks (abstract; Table 2 on page 448).
It would have been prima facie obvious to follow the details of the dosing regimen disclosed by Bassi. The skilled Artisan would have been motivated to do so because this regimen showed efficacy against bacillus Calmette-Guerin refractory carcinoma in situ (CIS) of the bladder. The skilled Artisan would have had a reasonable expectation of success because this would merely require dosing the patients as described by Bassi.
It is noted that the dosing regimen disclosed by Bassi lasted 6 consecutive weeks; however, the dosing schedule recited in the instant claims is continued for 12 consecutive weeks.
Nichols, in the analogous art of cancer chemotherapeutics, discloses that standard clinical trials may be used to optimizing dose and dosing frequency for any particular compound (0183).
It would have been prima facie obvious for one having ordinary skill in the art to test several different dosing protocols in order to optimize efficacy of treatment. The skilled Artisan would have been motivated to do so in order to find the best treatment dose and schedule. See MPEP 2144.05(II)(A) and Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") Testing different dosing schedules is considered routine in the art, therefore the examiner does not consider the limitation requiring the paclitaxel-HA conjugate to be administered for 12 weeks to patentably define over the prior art absent unexpected results.
The instant claims recite the intended outcome that the patient at the end of the 12 consecutive weeks of treatment has a 75% probability to be negative for both endoscopic examination and bioptic analysis as the patient did not have any tumor cell detectable at bladder level after cytology of the mucosa and urothelium. As explained above, it would have been prima facie obvious to extend duration of treatment with the paclitaxel-HA conjugate for 12 weeks as part of the process of discovering the optimal treatment regimen. The probability of being negative for both endoscopic examination and bioptic analysis due to no detectable tumor cells at bladder level is an outcome that is derived from following obvious and routine steps to optimize treatment protocol. This outcome is a natural consequence of the combination of prior art elements and for this reason, the intended outcome does not patentably define over the cited prior art. See MPEP 2145(II): "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). See also MPEP 2112: Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination.
The patient population disclosed by Bassi is bladder tumor patients diagnosed with CIS that is non-responsive to bacillus Calmette-Guerin.
Claims 5-13 requires that the paclitaxel prodrug is formed by the method recited in the claims. This is considered product by process language and does not further limit the claimed method of treating non-muscle invasive bladder cancer beyond the structure implied by the recited steps. According to MPEP 2113: product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. The examiner also notes that this step is taught in the method of making the paclitaxel-HA conjugate in example 5 of the ‘584 patent. This is a step in making the paclitaxel-HA used in the ‘584 invention and therefore the product by process language recited in claim 19 is encompassed by the ‘584 claims.
Claims 7, 8, 11, and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 7,897,584 (cited in the IDS filed 12/14/2023) in view of Bassi et al. (Journal of Urology Vol 185, pp 445-449; publication year: 2011; cited in the IDS filed on 12/14/2023) and Nichols et al. (US 2005/0080075; publication date: 04/14/2005; cited in the IDS filed 12/14/2023) as applied to claims 1, 2, 5, 6, 9, 10, 13, and 14 above and further in view of Elder et al. (US 2002/0169176; publication date: 11/14/2002; cited in the IDS filed 12/14/2023).
The relevant limitations of the ‘584 patent and the disclosures of Bassi and Nichols are set forth above. The claims of the ‘584 patent are silent with respect to the paclitaxel prodrug being formulated in sterile isotonic water containing 5% glucose. Bassi discloses that a paclitaxel-HA conjugate is soluble in 5% aqueous glucose solution (page 446), but does not mention that the solution is sterile and isotonic.
Elder discloses that compositions for injection can be formulated in 5% glucose in sterile water (0301).
Noting that the claims of the ‘584 patent embrace compositions for injection (claim 20) having pharmaceutically acceptable diluents (claim 20), it would be prima facie obvious to formulate the paclitaxel prodrug embraced by the ‘584 patent in 5% glucose in sterile water because one having ordinary skill in the art would recognize such a formulation as suitable. See MPEP 2144.07.
Response to Arguments
Applicant's arguments as well as the affidavits, each filed 08/13/2025 have been fully considered but they are not persuasive with regard to the nonstatutory double patenting rejections over US Application Nos 17/917,653 and 17/916,645 and US Patent No. 7,897,584.
On page 11 of the remarks, Applicant argues that the ‘653 and ‘645 applications are later filed and if a provisional obviousness-type double patenting rejection is the only rejection remaining, the Examiner should withdraw the obviousness-type double patenting rejection in the earlier filed application (in this case, the present application).
This argument is not persuasive because the rejection over the ‘653 and ‘645 applications is not the only rejection remaining.
On page 11, Applicant argues that the prior art discloses various possible binding sites on paclitaxel to obtain biologically active derivatives such as acetate derivatives at C2’ and C7 or succinic anhydride at C2’ and C7.
The examiner notes that any disclosure of alternative spacer moieties other than 4-bromobutyric acid is not relevant to the reasoning underlying the obviousness conclusion because these references are not the closest prior art. The closest prior art, De Luca discloses the 4-bromobutyric acid spacer. Additionally, applicant has noted the same two possible sites where the 4-bromobutyric acid could react with paclitaxel as noted by the examiner in the rejection. The examiner maintains that this is not an inordinately large number of possible choices, and in fact it is a small, finite number of options. See MPEP 2143(I)(E). The Examiner also directs attention to Merck &Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Circ. 1989), which states with regards to its more than 1200 combinations: that the prior art “discloses a multitude of effective combinations does not render any particular formulation less obvious. This is especially true because the claimed composition is used for the identical purpose taught by the prior art.” Furthermore, it is noted that Applicants do not identify any secondary consideration demonstrating criticality or anything unexpected about the combination of two known prior art pharmaceutical agents.
On page 12, Applicant argues that the pending claims recite a paclitaxel prodrug that consists of a conjugate between paclitaxel and hyaluronic acid (HA) by means of a 4-bromobutyric acid spacer at the C2’ position only. Applicant argues that this language excludes any other type of bond between paclitaxel and spacer. Applicant argues further on page 12, that this distinction is essential as De Luca (and Bassi) disclose a synthetic rout yielding a prodrug that contains a significant amount of di-Br-paclitaxel. Applicant explains that this occurs because the spacer, in the synthesis process, reacts with both hydroxyl groups at C2’ and C7 of paclitaxel, forming an intermediate that subsequently binds to HA chains, resulting in an inactive crosslinked HA/paclitaxel conjugate with no anti-tumoral activity. Applicant cites declarations filed in a copending application, US Serial No. 17315962. Applicant notes on page 12 of the remarks that the declaration filed 04/29/2024 in the ‘962 application shows that the synthesis disclosed in Deluca ‘584 yields a derivative containing at least 5% of di-Br-paclitaxel. This results in a paclitaxel prodrug that, as demonstrated by the Rule 132 Declaration filed on 10/22/2025 in the ‘962 application, is significantly less active than the prodrug of the claimed invention, precisely due to the presence of the inactive crosslinked HA/paclitaxel lacking antitumoral activity.
The examiner notes that US Serial No. 17315962 is not in the continuity chain of the instant Application.
This argument is not persuasive because the examiner respectfully disagrees with Applicant’s opinion that the language “wherein the paclitaxel prodrug consists of a conjugate between paclitaxel and hyaluronic acid (AH) by means of a 4-bromobutyric acid spacer, said HA being bound indirectly to the paclitaxel through an ester bond between a carboxyl of the AH and the 4-bromobutyric acid spacer in turn bound with an ester bond through its carboxyl to the hydroxyl group of the C2’ of paclitaxel” excludes all di-Br-paclitaxel impurities. The examiner reads the above language to limit the prodrug to a conjugate containing the linkage expressly described in the claim but not to exclude the presence of other moieties. Moreover, this also appears to be the broadest reasonable interpretation in view of the declaration filed 041/29/2024 in the ‘962 application because the evidence contained therein establishes the method employed in the instant application to result in a conjugate containing at least 0.8% di-Br-paclitaxel. Although characterized by Declarant as negligible, it is unambiguously present in the conjugate according to the instant invention.
Insomuch as this may be an assertion of unexpected results, please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Additionally, evidence of unexpected properties must be commensurate in scope with the claims.
The examiner notes the improved performance of the conjugate synthesized according to the method detailed in the instant specification; however, the data are not commensurate in scope with the claims. The recitation “wherein the nucleophilic substitution of the carboxyl of HA with the bromine of said spacer is subsequently obtained by direct contact in an anhydrous environment with a salt of tetrabutylammonium of HA” does not narrow the scope to exclude the ‘584 patent (De Luca) because this step is also carried out in the synthesis of the ‘584 conjugate.
On pages 12-13, Applicant argues that Bassi discloses a paclitaxel derivative different from the derivative according to the claimed invention.
This argument is not persuasive because Bassi was not cited for teaching the claimed paclitaxel HA conjugate, this limitation is taught by the claims of the ‘584 patent (De Luca). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
On pages 14-16, Applicant describes a study by Brooks, Sternberg, and Skinner, which arrive at a different treatment protocol for a different active agent (Gemcitabine).
As an initial matter, these documents have not been cited in an IDS. The listing of references in the arguments is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Importantly, these references discussing gemcitabine treatment protocols are not relevant to the current grounds of rejection because they are not the closest prior art.
Also, here the examiner is responding to Applicant’s position that other obvious choices besides extending treatment duration were known to one of ordinary skill and therefore extending treatment duration is non-obvious: See MPEP 2143.01(I): The disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention. In In re Fulton, 391 F.3d 1195, 73 USPQ2d 1141 (Fed. Cir. 2004), the claims of a utility patent application were directed to a shoe sole with increased traction having hexagonal projections in a "facing orientation." 391 F.3d at 1196-97, 73 USPQ2d at 1142. The Board combined a design patent having hexagonal projections in a facing orientation with a utility patent having other limitations of the independent claim. 391 F.3d at 1199, 73 USPQ2d at 1144. Applicant argued that the combination was improper because (1) the prior art did not suggest having the hexagonal projections in a facing (as opposed to a "pointing") orientation was the "most desirable" configuration for the projections, and (2) the prior art "taught away" by showing desirability of the "pointing orientation." 391 F.3d at 1200-01, 73 USPQ2d at 1145-46. The court stated that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." Id. In affirming the Board’s obviousness rejection, the court held that the prior art as a whole suggested the desirability of the combination of shoe sole limitations claimed, thus providing a motivation to combine, which need not be supported by a finding that the prior art suggested that the combination claimed by the applicant was the preferred, or most desirable combination over the other alternatives. Id. See also In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016).
In Ruiz v. A.B. Chance Co., 357 F.3d 1270, 69 USPQ2d 1686 (Fed. Cir. 2004), the patent claimed underpinning a slumping building foundation using a screw anchor attached to the foundation by a metal bracket. One prior art reference taught a screw anchor with a concrete bracket, and a second prior art reference disclosed a pier anchor with a metal bracket. The court found motivation to combine the references to arrive at the claimed invention in the "nature of the problem to be solved" because each reference was directed "to precisely the same problem of underpinning slumping foundations." Id. at 1276, 69 USPQ2d at 1690. The court also rejected the notion that "an express written motivation to combine must appear in prior art references…." Id. at 1276, 69 USPQ2d at 1690.
In the instant case, the fact that in some studies the investigators choose to study a dose or combination with other actives rather than extending the dosing schedule does not negate the obviousness of the instant invention, as claimed. The examiner maintains the obviousness conclusion exactly as set forth in the rejection. One having ordinary skill in the art would have been motivated to explore other doses and durations as a routine step in optimizing efficacy of any active agent. The examiner disagrees with this position that one would have had no motivation to double the number of administrations of the conjugate if clinical studies with it had already shown that such doubling provides worse results. The clinical studies that Applicant refers to were of a totally different drug, gemcitabine. One of ordinary skill in the art, i.e. a collaborative team of physicians and Ph.D. level scientists would definitively not just decide that one study was just good enough and never attempt to make further improvements. They would have done exactly the opposite. The Federal Circuit in Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324, 1330, 92 USPQ2d, 1849, 1854 (Fed. Cir. 2009) discussed the role of common sense in the determination of obviousness. The district court had cited KSR for the proposition that "[a] person of ordinary skill is also a person of ordinary creativity, not an automaton," and found that "the final step [of the claimed invention] is merely the logical result of common sense application of the maxim ‘try, try again.’" In affirming the district court, the Federal Circuit undertook an extended discussion of common sense as it has been applied to the obviousness inquiry, both before and since the KSR decision. In the instant case, the person of ordinary skill in the art noted above is a researcher who would be passionate about improving quality of life and survival of cancer patients, and therefore would be highly motivated to explore all possible avenues for treatment. Studying different doses and durations of exposure are some of the most basic ways to explore efficacy of any drug. "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). In the instant case, it would have been obvious to explore doses and treatment duration around those disclosed by Bassi in order to achieve outcomes that are not merely “satisfactory” but if possible even more effective.
On page 16, Applicant states that the above remarks are supported by the attached 37 CFR 1.132 declaration of Giorgio Mosconi.
The declaration presents exactly the same arguments addressed by the examiner in the preceding paragraphs and are not persuasive for the reasons detailed 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 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.
Claims 5, 6, 9, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over De Luca et al. (US 7,897,584; cited in the IDS filed 12/14/2023) in view of Bassi et al. (Journal of Urology Vol 185, pp 445-449; publication year: 2011; cited in the IDS filed on 12/14/2023) and further in view of Nichols et al. (US 2005/0080075; publication date: 04/14/2005; cited in the IDS filed 12/14/2023).
Claims 7, 8, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over De Luca et al. (US 7,897,584; cited in the IDS filed 12/14/2023) in view of Bassi et al. (Journal of Urology Vol 185, pp 445-449; publication year: 2011; cited in the IDS filed on 12/14/2023), Nichols et al. (US 2005/0080075; publication date: 04/14/2005; cited in the IDS filed 12/14/2023) as applied to claims 11, 12, 16, 19, 23, and 24 above, and further in view of Elder et al. (US 2002/0169176; publication date: 11/14/2002; cited in the IDS filed 12/14/2023).
The claims are rejected as obvious over De Luca, Bassi, Nichols, and Elder exactly as set forth in the double patenting rejections above.
Response to Arguments
Applicant's arguments filed 08/13/2025 have been fully considered but they are not persuasive.
On page 17, Applicant traverses the obviousness rejections for the same reasons as detailed in the remarks traversing the double patenting rejections.
This is not persuasive for the reasons detailed in the examiner’s response to the traversal of the double patenting rejections.
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 KATHERINE PEEBLES whose telephone number is (571)272-6247. The examiner can normally be reached Monday through Friday: 9 am to 3 pm.
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, Ali Soroush can be reached at (571)272-9925. 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.
/KATHERINE PEEBLES/ Primary Examiner, Art Unit 1617