The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-19 are pending and under consideration.
Priority: This application is a CON of U.S. Application 18351241, filed July 12, 2023, abandoned, which is a CON of U.S. Application 17396028, filed August 6, 2021, now U.S. Patent 11746348, which is a CON of U.S. Application 16816741, filed March 12, 2020, now U.S. Patent 11085043, which is a CON of U.S. Appl. 15844801, filed December 18, 2017, abandoned, which is a CON of U.S. Appl. 14408272, filed December 15, 2014, now U.S. Patent 9902952, which is a 371 of PCT/IT2012/000193, filed June 22, 2012.
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 1-19 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 a method of treating Veno-Occlusive Disease (VOD) comprising administering to a patient in need thereof a defibrotide formulation as noted in the instant claim(s), does not reasonably provide enablement for a method of preventing VOD comprising administering to a patient in need thereof a defibrotide formulation as noted in the instant claim(s). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Instant claim 1 and the dependent claims are drawn to a method of preventing VOD comprising administering to a patient in need thereof the noted defibrotide formulation.
The instant specification does not adequately describe a method of administering defibrotide what when administered allow for preventing any VOD condition in any patient in need thereof, wherein sad method has been shown or can be reasonably be predicted to produce beneficial effect. Hepatic VOD is a severe complication after hematopoietic stem cell transplantation (HSCT); different drugs with different mechanisms of action have been tried to prevent hepatic VOD; however, it is uncertain whether high-quality evidence exists to support any prophylactic therapy (Cheuk et al. p. 1). Therefore, for the claimed invention, it would require an undue burden of experimentation for a skilled artisan to determine exactly which VOD conditions, which patients, and at which dosing regimen(s) have biological activity and therapeutic activity for preventing all VOD conditions in all patients.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). 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 of 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.
In this instance, and as noted above, hepatic VOD is a severe complication after hematopoietic stem cell transplantation (HSCT); different drugs with different mechanisms of action have been tried to prevent hepatic VOD; however, it is uncertain whether high-quality evidence exists to support any prophylactic therapy (Cheuk et al. p. 1). The quantity of experimentation would be large because the severity of VOD can vary among patients and the defibrotide formulation while having therapeutic effects in treating VOD may not prevent VOD. The specification provides no guidance as to how VOD is prevented by administering the defibrotide formulation to any patient. No working examples are present of the defibrotide formulation preventing any degree of VOD. The nature of the invention is such that while drugs may have activity in treating a disease condition may not have activity in preventing the condition. The state of the art is such that results from randomized controlled trials comparing various therapies, including defibrotide, for prophylaxis of hepatic VOD, there is insufficient evidence to support the use of noted therapies, including defibrotide (Cheuk et al. p. 1-2). Regarding defibrotide, there was a low quality of evidence of difference in the incidence of hepatic VOD between treatment and control groups for defibrotide; and there was a low quality of evidence of difference in survival between treatment and control groups for defibrotide; there was no data on quality of life for any trials; and there was no evidence of difference in the frequency of adverse events between treatment and control groups except for one trial showing that defibrotide resulted in more adverse events compared with no treatment (Cheuk et al. p. 2). While defibrotide has been used with success in treating VOD and several studies have shown that it also may prevent VOD; studies are ongoing and defibrotide currently is not a U.S. Food and Drug Administration (FDA)-approved treatment for the prevention of VOD (Sosa p. 510). Although much has been discovered about VOD…no standard prevention or treatment currently exists for this serious complication of transplantation; supportive care is provided for patients with moderate and severe VOD, but additional studies are needed so that VOD can be prevented in stem cell transplantation recipients, and so that patients who develop VOD have the best chance of survival (Sosa p. 510-511). Therefore, determining whether the administered defibrotide formulation has therapeutic value in a subject in need thereof for preventing any VOD condition is very unpredictable in nature. The relative level of skill in this art is very high. The predictability as to whether the administered defibrotide will have which activity and/or therapeutic activity in vivo for prevention of VOD is zero.
The instant specification fails to show actual reduction to practice preventing any VOD condition in any patient in need thereof, by administering the defibrotide formulation, and fails to provide adequate guidance on how to overcome the art-recognized difficult nature of this goal. Thus, one skilled in the art could not make and use the claimed invention for preventing any VOD as claimed.
When the factors are considered in their entirety, the Wands analysis dictates a finding of undue experimentation and thus, the claims are not enabled.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Fedeli et al. (US 4985552; IDS) in view of Bonomini (US 4649134; IDS) and Osterberg et al. (2003 International Journal of Toxicology 22: 377-380; IDS).
Fedeli et al. disclose defibrotide is defined as a sodium salt of low molecular weight nucleotidic fractions obtained by extraction from animal organs and has known therapeutic properties, including as treatment of acute renal insufficiency (to US 4649134; Bonomini) (at least col. 1 lines 15-48). It is disclosed that processes for obtaining defibrotide, disclosed in U.S. Patent Nos. 3770720 and 3899481, comprise the extraction and the partial degradation of the deoxyribonucleic acids by means of protonic degradation of nucleic acids, where the yields of defibrotide are relatively low and the product is often accompanied by degradation products (at least col. 3 lines 38-49). Fedeli et al. disclose providing a process for providing defibrotide that addresses the problems and drawbacks of previous processes, where the defibrotide provided is of substantial uniformity from one production batch to another, the complete usefulness and reliability of the obtained defibrotide product for therapy in human beings (at least col. 3 lines 29-37, 50-60). It has been surprisingly found that the process by operating under more controlled conditions of aggregation, raw nucleic acids can be depolymerized in an advantageous manner, thereby reducing to a minimum the formation of degradation products (at least col. 3 lines 62-66). The defibrotide having substantial uniformity also fully fulfills its known pharmacological and therapeutic properties and is particularly useful for the therapeutic uses cited (at least col. 2 lines 4-10). Fedeli et al. do not explicitly teach a composition comprising the defibrotide with pharmaceutical excipients, for injection.
As also noted by Fedeli et al., Bonomini discloses a composition containing defibrotide for treatment of states of acute renal insufficiency. Bonomini discloses that the composition permits, in the case of acute renal insufficiencies characterized by the presence of thrombotic microangiopathy, not only the evolution of the clinical situation towards the chronicity to be stopped, but also, in a number of cases, a complete remission of the disease to be obtained (at least col. 1 lines 1-45). Bonomini discloses a composition for injection comprising defibrotide (200 mg), trisodium citrate dihydrate, parabens (i.e. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate), and water (2.5 mL) (col. 4 example 1). Therefore, Bonomini can be deemed to disclose a liquid defibrotide formulation comprising a concentration of at least 80 mg/mL, at a pH from about 7-8. Bonomini discloses the pharmaceutical compositions comprising defibrotide are prepared for administration in a pharmaceutically suitable form…in general non-toxic and pharmacologically inactive substances…(at col. 15-34). Bonomini does not explicitly teach that the composition for injection comprises only defibrotide (200 mg), trisodium citrate dihydrate, and water (2.5 mL).
Osterberg et al. disclose that excipients are essential components of drug products, but are also potential toxicants (p. 377). Osterberg et al. disclose examples of excipient-induced toxicities include hypersensitivity reaction produced in susceptible individuals by such excipients including among others parabens (p. 377-378).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to
arrive at a defibrotide formulation comprising defibrotide (200 mg), sodium citrate, and water for injection (2.5 mL), where the liquid defibrotide formulation has a concentration of at least 80 mg/mL, where the defibrotide has substantial uniformity and reasonably has a potency of about 25 to about 35 IU/mg and a pH from about 7-8, and administer the defibrotide formulation to a patient in need thereof for treating acute renal insufficiencies characterized by the presence of thrombotic microangiopathy, thereby arriving at the claimed method of preventing VOD comprising administering to a patient in need thereof a defibrotide formulation comprising defibrotide (200 mg), sodium citrate, and water for injection (2.5 mL), where the liquid defibrotide formulation has a concentration of at least 80 mg/mL, where the defibrotide has substantial uniformity and reasonably has a potency of about 25 to about 35 IU/mg and a pH from about 7-8. One of ordinary skill would have a reasonable expectation that the defibrotide prepared by the process of Fedeli et al. and formulated as a composition for injection has a potency of about 25 to about 35 IU/mg and a pH from about 7-8 since Fedeli et al. disclose a defibrotide that is or appears structurally the same as the claimed defibrotide and can be formulated in a pharmaceutical composition including 200 mg defibrotide and 2.5 mL water for injection (instant claims 1-19). Regarding the motivation to omit methyl p-hydroxybenzoate and propyl p-hydroxybenzoate from the defibrotide formulation, MPEP 2144.04 notes that the elimination or omission of an element and its function is obvious if the function of the element is not desired. In this instance, it would have been obvious to exclude methyl p-hydroxybenzoate and propyl p-hydroxybenzoate from the defibrotide formulation for injection and arrive at a defibrotide formulation comprising just defibrotide (200 mg), sodium citrate, and water for injection (2.5 mL) because it is disclosed that parabens are potential toxicants and may produce hypersensitivity reaction(s) in susceptible individuals (Osterberg et al.).
Additionally, while the instant claims additionally recite process or method steps in the wherein clause, it is noted that the recited method steps are intended uses and/or results to be achieved that indicate the potency of the liquid defibrotide formulation. The instant claims are still method claims drawn to a method for administering the defibrotide formulation having a potency, regardless of how the potency is determined. In this instance, one of ordinary skill would have a reasonable expectation that the defibrotide prepared by the process of Fedeli et al. and formulated as a composition for injection has the recited potency of about 25 to about 35 IU/mg and a pH from about 7-8 since Fedeli et al. disclose a defibrotide that is or appears structurally the same as the claimed defibrotide and can be formulated in a pharmaceutical composition including 200 mg defibrotide and 2.5 mL water for injection (instant claims 1-19).
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.
Claims 1-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11236328 (‘328). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘328 patent claims are drawn to a method for treating VOD comprising administering to a patient in need thereof a defibrotide formulation consisting of defibrotide, sodium citrate, and water for injection, having a potency of 25 to 35 IU/mg, and a concentration of at least 80 mg/mL.
Claims 1-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11085043 (‘043). Although the claims at issue are not identical, they are not patentably distinct from each other because the invention of the instant claims and the '043 patent claims relate to a defibrotide formulation having the same composition, potency of 25 to 35 IU/mg and concentration of at least 80 mg/mL, used for the same purpose. The specification of the '043 patent discloses defibrotide is used for the treatment of venous occlusive disease (VOD) (col. 1 lines 30-32). Therefore, it would have been obvious to administer the defibrotide formulation of the '043 patent claims to a patient in need thereof for treating VOD, thereby arriving at the instant claims. The components and/or elements of the defibrotide formulation recited in the instant dependent claims are all also recited in the '043 patent claims.
Claims 1-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11746348 (‘348). Although the claims at issue are not identical, they are not patentably distinct from each other because the invention of the instant claims and the '348 patent claims relate to a defibrotide formulation having the same composition, potency of 25 to 35 IU/mg and concentration of at least 80 mg/mL, used for the same purpose. The specification of the '348 patent discloses defibrotide is used for the treatment of venous occlusive disease (VOD) (col. 1 lines 35-37). Therefore, it would have been obvious to administer the defibrotide formulation of the '348 patent claims to a patient in need thereof for treating VOD, thereby arriving at the instant claims. The components and/or elements of the defibrotide formulation recited in the instant dependent claims are all also recited in the '348 patent claims.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Marsha Tsay whose telephone number is (571)272-2938. The examiner can normally be reached on M-F.
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, Manjunath N. Rao can be reached on 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Marsha Tsay/Primary Examiner, Art Unit 1656
Prosecution Insights