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
Claims 1, 2, 10, 11, 13-15, 21-24, 36, 42, 50-51, 53-55 and 61 are pending. Claim 1 has been amended to incorporate a broad dosage amount of about 1-1500 mg of the claimed compound. Therefore, Claims 1, 2, 10, 11, 13-15, 21-24, 36, 42, 50-51, 53-55 and 61 are examined on the merits.
Priority
This application is a U.S. National Stage Application of International Application No. PCT/US20/44037, filed July 29, 2020: which claims the benefit of priority to U.S. Provisional Patent Application No. 62/88 1,225, filed July 31, 2019; U.S. Provisional Patent Application No. 62/926,175, filed October 25, 2019; and U.S. Provisional Patent Application No. 63/020,239, filed May 5, 2020.
Information Disclosure Statement
No Information Disclosure Statement was filed with Applicant’s current response.
Response to Arguments
Applicant's arguments filed 9/22/2025 have been fully considered but they are not persuasive.
A. Applicant alleges that the rejections improperly rely on secondary references for ODP rejections
Applicant argues throughout the 9/22/2025 remarks that the rejection improperly relied on Remington’s and Subasinghe to “supply patentably distinguishing features,” thereby converting the nonstatutory double patenting (ODP) rejection into a rejection under 35 U.S.C. §103. However, this leg of Applicant’s arguments is contrary to the legal requirements for ODP rejections. Proper ODP analysis compares the claims of a reference patent or copending U.S. application with the claims under examination to determine whether they are patentably distinct, i.e., whether they are obvious variants of what was previously or currently claimed in another patent or copending application, respectively. When determining this, the knowledge of a person of ordinary skill in the art (POSA) may be considered to assess whether the difference between the claims would have been obvious. Secondary references may be cited in ODP rejections and properly used for the purpose of demonstrating the knowledge of a POSA. Remington’s and Subasinghe were cited to demonstrate that limitations such as oral dosage form, dosage ranges, and administration regimens represent conventional and routine variations applicable to already claimed subject matter. Thus, Applicant’s argument that the rejection is legally improper is not persuasive.
B. Applicant asserts reference claims cannot be used as prior art and do not teach all claimed limitations
Applicant argues that the patented claims cannot be relied on as prior art or to reject the current invention because they do not represent prior art and they do not expressly teach all claimed limitations. Applicant repeatedly asserts that the reference claims do not expressly recite oral dosage, oral administration or the specific dosage ranges instantly claimed and, therefore, cannot support an ODP rejection. First, the patent claims are not being used as prior art as alleged by Applicant. Second, nonstatutory obviousness-type double patenting does not require identical claim language or express recitation of every limitation. The inquiry is whether the current subject matter is patentably distinct from what was previously claimed. In this case, the limitations that encompass routine formulation choices, administration routes, or dosage optimization do not grant patentable distinction to the same compound or its use for the same therapeutic target and the same disease indication.
C. Applicant asserts ranges unpredictable in the art
Applicant asserts nonobviousness due to unpredictability of ranges disclosed in the art. However, selection of dose amount and frequency constitutes routine optimization of a result-effective variable, particularly where overlapping or encompassing ranges are disclosed and where the claims are directed to the same therapeutic use of the same or closely related compounds. Safety, tolerability, and dose-escalation data reflect optimization and do not establish patentable distinctness under nonstatutory ODP doctrine.
D. Unexpected results alleged
Applicant asserts that pharmacokinetic, pharmacodynamic and safety data demonstrate unexpected results. This is not persuasive. The burden is on Applicant to establish results are unexpected and significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). In this case, the pharmacokinetic data presented in the as-filed specification does not constitute an unexpected result. Unexpected results do not merely show routine optimization of what was previously claimed where the optimization is not unexpected. Furthermore, the claimed invention is not commensurate in scope with the data proffered to demonstrate unexpected results. See MPEP 716.02(b). Accordingly, the data presented cannot be relied upon to establish unexpected results.
E. Applicant asserts compound structures are too complex to be rendered obvious
Applicant provides discussion about alleged structural and bioisosteric complexity to argue that the instant claims are patentably distinct from ‘418 and ‘610. However, the rejection requirement is not based on complexity of medicinal chemistry per se but whether the claims would improperly extend exclusivity beyond the term of a patent invention or obvious variant thereof. See MPEP §804. Indeed, the prior art (Remington’s and Subasinghe) demonstrate that the changes now claimed by Applicant are merely routine and obvious variations of what was already claimed as outlined in the rejections below.
Double Patenting
Rejections maintained
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, 2, 10, 11, 13-15, 21-24, 36, 42, 50-51, 53-55, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,021,458 (reference claims) in view of Gennaro, Alfonso. (Remington’s pharmaceutical Sciences. Easton, PA: Mack Pub. Co., 1990) (“Remington”) and Subasinghe et al. (US 20050004031 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the reference claims are drawn to pharmaceutical compositions containing compounds and pharmaceutically acceptable carrier. An example compound is
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. See reference Claims 1 and 9.
The reference claims do not expressly claim oral dosage forms comprising the compound as required by Claim 1 or a method of therapeutically treating PNH as a disease or condition characterized by aberrant complement system activity as required by Claim 24.
However, the reference claims clearly indicate that the compounds have pharmaceutical use given that the reference claims disclose, in addition to the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds or the salts. See reference Claims 1 and 9. The utility of the reference compounds is disclosed as effective inhibitors of the complement system useful in therapeutic methods for treating or preventing a disease or condition characterized by aberrant activity of the complement system (see abstract) including paroxysmal nocturnal hemoglobinuria (PNH) (see col. 258, l. 64-65). Clearly the compounds are disclosed as drugs suitable for administration. In this regard, Remington teaches drug substances are most frequently administered orally by means of solid dosage forms such as tablets and capsules. See p. 1633. Tablets remain popular as a dosage form because of the advantages afforded both to the manufacturer (e.g., simplicity and economy of preparation, stability and convenience in packaging, shipping and dispensing) and the patient (e.g., accuracy of dosage, compactness, portability, blandness of taste and ease of administration). Additionally, Subasinghe discloses inhibitors of complement system and proteins formed by the system (e.g., C3a and C5a) are suitably orally administered for treating diseases implicated in undesirable initiation of the complement system such as PNH. See Subasinghe, 0003,0008,0170. Accordingly, a person of ordinary skill in the art (POSITA/POSA) would have recognized that the compositions containing compounds of the reference claims may be formulated in oral dosage forms to provide administrable compositions of the compounds in the most frequently used dosage forms such as tablets and capsules. The artisan would have desired to provide oral tablets and capsules as suitable dosage forms for administration. Further, the artisan would have found it obvious to formulate the compounds in a tablet dosage form because of known advantages such as accuracy of dosage, compactness, portability, blandness of taste or ease of administration. Further given that inhibitors of the complement system can be administered orally, the POSA would have further understood that the reference compounds may be formulated into orally administrable compositions to provide the therapeutic utility of the compounds to inhibit the complement system.
Claims 1, 2, 10-11, and 13-15 and Claims 42, 50-51, and 53-55 (amounts)
Claim 1 further recites comprising about 1 mg to about 1500 mg. Claim 2 limits claim 1, comprising about 1 mg to about 1200 mg, about 1 mg to about 1000 mg, about 1 mg to about 800 mg, about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, or about 1 mg to about 200 mg of the compound or a pharmaceutically acceptable salt. Claim 10 limits claim 1, comprising about 1 mg to about 100 mg of the compound or a pharmaceutically acceptable salt. Claim 11 limits claim 1, comprising about 10 mg or about 30 mg of the compound or a pharmaceutically acceptable salt. Claim 13 limits claim 1, comprising about 100 mg of the compound or a pharmaceutically acceptable salt. Claim 14 limits claim 1, comprising about 200 mg of the compound or a pharmaceutically acceptable salt. Claim 15 limits claim 1, comprising about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg of the compound or a pharmaceutically acceptable salt.
The Subasinghe reference teaches the dosage of the compounds of the present invention that will be most suitable for prophylaxis or treatment will vary with the form of administration (e.g., orally or parenterally – see 0170), the particular compound chosen and the physiological characteristics of the particular patient under treatment. Generally, small dosages may be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is reached. The therapeutic human dosage, based on physiological studies using rats, may generally range from about 0.01 mg to about 600 mg/kg of body weight per day, and all combinations and subcombinations of ranges therein. Alternatively, the therapeutic human dosage may be from about 0.4 mg to about 10 g or higher, and may be administered in several different dosage units from once to several times a day. See 0169.
The claimed dosage ranges represent routine optimization of a known class of therapeutic compounds disclosed in the art. Specifically, Subasinghe teaches that compounds inhibiting the complement system are therapeutically useful for treating diseases such as PNH, Subasinghe further discloses a broad range of human therapeutic doses may range from about 0.4 mg to about 10 g or higher, and may be administered once to several times a day. This range overlaps and encompasses all of the claimed dosage ranges, including an amount as low as 1 mg and as high as 1500 mg, depending on the formulation and patient characteristics. Furthermore, Subasinghe explicitly teaches that the optimal dose will depend on the route of administration, the compound selected, and patient-specific factors, and should be titrated as needed. Such guidance would have led a POSA to systematically explore doses within the tight range through routine experimentation to arrive at a therapeutically effective dose with minimal adverse effects. As such, the specific amounts recited in the claims (e.g., 10 mg, 30 mg, 100 mg, 600 mg, etc.) would have been obvious variations within the range taught by the prior art, and would represent nothing more than optimization of a result effective variable. Therefore, in view of the teachings of Subasinghe regarding the therapeutic application of complement inhibitors their broad dosage range, and guidance on patient-specific adjustments, the claimed amounts would have been obvious to a POSA at the time the invention was filed. The POSA would have sought to formulate the dosage form to provide the desired dosage amount whether administered once or several times a day. These particular teachings meet the claimed dosage limitations for Claims 42, 50-51 and 53-55 which depend from Claim 24 are drawn to a method of treating a disease or condition.
Claimed 21-23 (dosage form)
Claim 21 limits claim 1, wherein the oral dosage form is a capsule. Claim 22 limits claim 1, wherein the oral dosage form is a tablet. Claim 23 limits claim 22. wherein the tablet is a coated tablet. As outlined above, the POSA would have recognized that the compositions containing compounds of the reference claims may be formulated in oral dosage forms to provide administrable compositions of the compounds in the most frequently used dosage forms such as tablets. The artisan would have desired to provide an oral tablet dosage form of the compounds because of known advantages such as accuracy of dosage, compactness, portability, blandness of taste or ease of administration. Further given that inhibitors of the complement system can be administered orally, the POSA would have further understood that the reference compounds may be formulated into orally administrable compositions to provide the therapeutic utility of the compounds. Regarding the coated tablet limitation, Remington discloses tablets can be made into controlled-release formulas using the polymer, hydroxypropylmethylcellulose (HPMC), both as an aid to prolong the release from the tablet, as well as a film-former in the tablet coating. Thus, the POSA would have further found it obvious to formulate a coated tablet in order to provide a formulation wherein the release of the active compound can be controlled.
Claims 24, 36, 42, 50-51, 53-55 and 61 (method)
With respect to the method of treating PNH in Claim 24, the reference claims disclose compounds that act as effective inhibitors of the complement system. These inhibitors are described as useful in therapeutic methods for treating or preventing diseases or conditions characterized by aberrant complement system activity, such as paroxysmal nocturnal hemoglobinuria (PNH). Subasinghe supports this by teaching that such inhibitors are useful for treating diseases involving undesirable initiation of the complement system, including PNH. Therefore, the POSA would have found it obvious to formulate these compounds for oral administration to therapeutically treat PNH, a condition marked by abnormal or undesirable complement system activation.
Claim 36 limits claim 35, wherein the PNH is characterized by one or more of hemolytic anemia, thrombosis, and impaired bone marrow function. Subasinghe further teaches that, in addition to PNH, the inhibitors can be used to treat hemolytic anemia. Therefore, the POSA would have further found it obvious to treat a subject presenting with both hemolytic anemia and PNH such as the case wherein the PNH is characterized by hemolytic anemia. Given that the complement system inhibitors are useful for treating both conditions, the POSA would have reasonably understood that the inhibitors can be used to treat a subject wherein both conditions are present such as those with PNH characterized by hemolytic anemia.
As indicated above for Claims 2, 10, 11 and 13-15, the particular teachings from Subasinghe meet the claimed dosage limitations for Claims 42, 50-51 and 53-55 which depend from directly or indirectly Claim 24.
Claim 61 limits claim 24, wherein the compound or a pharmaceutically acceptable salt is administered once daily, twice daily, or three times daily. As mentioned above, Subasinghe discloses therapeutic doses may be administered once to several times a day. Therefore, the POSA would have at least found the claimed limitation of once a day to be obvious.
Claims 1, 2, 10, 11, 13-15, 21-24, 36, 42, 50-51, 53-55 and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,708,347 (reference claims) in view of “Remington” (Gennaro, Alfonso. Remington’s pharmaceutical Sciences. Easton, PA: Mack Pub. Co., 1990), and Subasinghe et al.(US 2005/0004031 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the reference claims are drawn to a method of treating PNH as a disease characterized by aberrant complement system activity comprising administering an effective amount of a compound or pharmaceutically acceptable salt thereof. An example compound is
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. See reference Claims 1-2, 4 and 6-9.
The reference claims do not expressly claim an oral dosage form comprising the compound or the administration of the oral dosage form as required by Claim 1 or Claim 24.
However, the reference claims disclose the compounds are administered to a subject to treat a disease characterized by aberrant complement system activity such as PNH. See reference Claim 1. Remington teaches drug substances are most frequently administered orally by means of solid dosage forms such as tablets and capsules. See p. 1633. Tablets remain popular as a dosage form because of the advantages afforded both to the manufacturer (e.g., simplicity and economy of preparation, stability and convenience in packaging, shipping and dispensing) and the patient (e.g., accuracy of dosage, compactness, portability, blandness of taste and ease of administration). Additionally, Subasinghe discloses inhibitors of complement system and proteins formed by the system (e.g., C3a and C5a) are suitably orally administered for treating diseases implicated in undesirable initiation of the complement system such as PNH. See Subasinghe, 0003,0008,0170. Accordingly, a person of ordinary skill in the art (POSITA/POSA) would have recognized that the compositions containing compounds of the reference claims may be formulated in oral dosage forms to provide orally administrable compositions of the compounds in the most frequently used dosage forms such as tablets and capsules. The POSA would have desired to provide oral tablets and capsules because they are popularly known as suitable dosage forms for administration of drugs. Further, the artisan would have found it obvious to formulate the compounds in a tablet dosage form because of known advantages such as accuracy of dosage, compactness, portability, blandness of taste or ease of administration. Further given that inhibitors of the complement system can be administered orally, the POSA would have further understood that the reference compounds may be formulated into orally administrable compositions to provide the therapeutic effect of the compounds to inhibit the complement system.
Claims 1, 2, 10-11, and 13-15 and Claims 42, 50-51, and 53-55 (amounts)
Claim 1 further recites comprising about 1 mg to about 1500 mg. Claim 2 limits claim 1, comprising about 1 mg to about 1200 mg, about 1 mg to about 1000 mg, about 1 mg to about 800 mg, about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, or about 1 mg to about 200 mg of the compound or a pharmaceutically acceptable salt. Claim 10 limits claim 1, comprising about 1 mg to about 100 mg of the compound or a pharmaceutically acceptable salt. Claim 11 limits claim 1, comprising about 10 mg or about 30 mg of the compound or a pharmaceutically acceptable salt. Claim 13 limits claim 1, comprising about 100 mg of the compound or a pharmaceutically acceptable salt. Claim 14 limits claim 1, comprising about 200 mg of the compound or a pharmaceutically acceptable salt. Claim 15 limits claim 1, comprising about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg of the compound or a pharmaceutically acceptable salt.
The Subasinghe reference teaches the dosage of inhibitors of complement system will vary with the form of administration (e.g., orally or parenterally – see 0170), the particular compound chosen and the physiological characteristics of the particular patient under treatment. Thus, the POSA would have found it obvious to formulate compositions containing the amounts of the inhibitor for administration at levels already known to be effective for complement system inhibition. The POSA would also have understood it to be routine to adjust the dosage as needed to achieve the desired therapeutic effect, taking into account factors such as route of administration, the specific inhibitor being used, and the patient’s physiological characteristics. According to Subasinghe, generally, small dosages may be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is reached. The therapeutic human dosage, based on physiological studies using rats, may generally range from about 0.01 mg to about 600 mg/kg of body weight per day, and all combinations and subcombinations of ranges therein. Alternatively, the therapeutic human dosage may be from about 0.4 mg to about 10 g or higher, and may be administered in several different dosage units from once to several times a day. See 0169. This range overlaps and encompasses all of the claimed dosage ranges, including an amount as low as 1 mg and as high as 1500 mg, depending on the formulation and patient characteristics. Furthermore, Subasinghe explicitly teaches that the optimal dose will depend on the route of administration, the compound selected, and patient-specific factors, and should be titrated as needed. Such guidance would have led a POSA to systematically explore doses within the tight range through routine experimentation to arrive at a therapeutically effective dose with minimal adverse effects. As such, the specific amounts recited in the claims (e.g., 10 mg, 30 mg, 100 mg, 600 mg, etc.) would have been obvious variations within the range taught by the prior art, and would represent nothing more than optimization of a result effective variable. Therefore, in view of the teachings of Subasinghe regarding the therapeutic application of complement inhibitors their broad dosage range, and guidance on patient-specific adjustments, the claimed amounts would have been obvious to a POSA at the time the invention was filed. The POSA would have sought to formulate the dosage form to provide the desired dosage amount whether administered once or several times a day. These particular teachings meet the claimed dosage limitations for Claims 42, 50-51 and 53-55 which depend from Claim 24 are drawn to a method of treating a disease or condition.
Claimed 21-23 (dosage form)
Claim 21 limits claim 1, wherein the oral dosage form is a capsule. Claim 22 limits claim 1, wherein the oral dosage form is a tablet. Claim 23 limits claim 22. wherein the tablet is a coated tablet. As outlined above, the POSA would have recognized that the compositions of the reference claims may be prepared in orally administrable dosage forms such as capsules and tablets because these are the most commonly used dosage formats. The artisan would have particularly provided a tablet dosage form because of known advantages such as accuracy of dosage, compactness, portability, blandness of taste or ease of administration.
Additionally, since complement inhibitors can be administered orally, the POSA would have reasonably expected that the compounds of the reference claims could be delivered in such a format while preserving therapeutic activity. Regarding the coated tablet limitation, Remington discloses tablets can be made into controlled-release formulas using the hydroxypropylmethylcellulose (HPMC), which functions both to prolong drug release and to act as a film-forming agent in the tablet coating. Accordingly, the POSA would have found it obvious to prepare the active compound in a coated tablet formulated to enable controlled release.
Claims 24, 36, 42, 50-51, 53-55 and 61 (method)
With respect to the method of treating PNH in Claim 24, the reference claims disclose compounds that act as effective inhibitors of the complement system. These inhibitors are described as useful in therapeutic methods for treating or preventing diseases or conditions characterized by aberrant complement system activity, such as paroxysmal nocturnal hemoglobinuria (PNH). Subasinghe supports this by teaching that such inhibitors are useful for treating diseases involving undesirable initiation of the complement system, including PNH. Therefore, the POSA would have found it obvious to formulate these compounds for oral administration to therapeutically treat PNH, a condition marked by abnormal or undesirable complement system activation.
Claim 36 limits claim 35, wherein the PNH is characterized by one or more of hemolytic anemia, thrombosis, and impaired bone marrow function. Subasinghe further teaches that, in addition to PNH, the inhibitors can be used to treat hemolytic anemia. Therefore, the POSA would have further found it obvious to treat a subject presenting with both hemolytic anemia and PNH such as the case wherein the PNH is characterized by hemolytic anemia. Given that the complement system inhibitors are useful for treating both conditions, the POSA would have reasonably understood that the inhibitors can be used to treat a subject wherein both conditions are present such as those with PNH characterized by hemolytic anemia.
As indicated above for Claims 2, 10, 11 and 13-15, the particular teachings from Subasinghe meet the claimed dosage limitations for Claims 42, 50-51 and 53-55 which depend from directly or indirectly Claim 24.
Claim 61 limits claim 24, wherein the compound or a pharmaceutically acceptable salt is administered once daily, twice daily, or three times daily. As mentioned above, Subasinghe discloses therapeutic doses may be administered once to several times a day. Therefore, the POSA would have at least found the claimed limitation of once a day to be obvious.
C. Claims 1, 2, 10, 11, 13-15, 21-24, 36, 42, 50-51, 53-55 and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,866,418 (reference claims) in view of Nathan Brown ((2012). Front Matter. In Bioisosteres in Medicinal Chemistry (eds R. Mannhold, H. Kubinyi, G. Folkers and N. Brown). https://doi.org/10.1002/9783527654307.fmatter), Remington (Gennaro, Alfonso. Remington’s pharmaceutical Sciences. Easton, PA:Mack Pub. Co., 1990), and Subasinghe et al. (US 2005/0004031 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the reference claims are drawn to a method of treating a disease characterized by aberrant complement system activity including PNH by administering similar compounds in pharmaceutical compositions containing them. The instant compound is
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wherein the reference compound is
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. See reference Claims 1 and 5.
The reference claims do not expressly claim the exact compound, an oral dosage form comprising the compound or the administration of the oral dosage form.
With regard to the difference in compounds, the instant structure
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as compared to the reference structure
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differ in two aspects: the instant compound has a fluorine atom in place of a hydrogen on the pyridine ring, and a hydrogen in the place of a methyl on the phenylene ring. However, it is well established in medicinal chemistry that such modifications fall within the principals of bioisosterism. These principals provide the framework for substituting one functional group for another enabling chemist to rationally design novel therapeutic agents through routine replacement of known substituents with commonly used bioisosteres. For example, Brown discloses “[o]ne of the most significant approaches to assist in efficiently navigating the available chemistry space is that of bioisosteric replacement” (see p. 2). Substitutions between fluorine and hydrogen and hydrogen and methyl are textbook examples of monovalent bioisosteric replacements. Specifically, Brown teaches the following classical monovalent bioisosteres where groups in each row are equivalent:
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See p. 7, Table 1.3.
This specifically identifies F, OH, NH, CH3, and H as equivalent classical monovalent bioisosteres, thereby supporting substitutions such as H[Wingdings font/0xE0]F or CH3[Wingdings font/0xE0]H as routine design strategies.
A person of ordinary skill in the art (POSITA/POSA) would have found it obvious to substituted a hydrogen with a fluoride and a methyl with a hydrogen in the reference compound arriving at the current compound because Brown teaches these atoms as classical equivalent monovalent bioisosteres. The artisan would have recognized that such substitutions are routinely employed for rational compound design in drug development.
With regard to oral compositions for oral administration, the reference claims disclose the compounds are administered to a subject to treat a disease characterized by aberrant complement system activity including PNH. See reference Claim 1. Remington teaches drug substances are most frequently administered orally by means of solid dosage forms such as tablets and capsules. See p. 1633. Tablets remain popular as a dosage form because of the advantages afforded both to the manufacturer (e.g., simplicity and economy of preparation, stability and convenience in packaging, shipping and dispensing) and the patient (e.g., accuracy of dosage, compactness, portability, blandness of taste and ease of administration). Additionally, Subasinghe discloses inhibitors of complement system and proteins formed by the system (e.g., C3a and C5a) are suitably orally administered for treating diseases implicated in undesirable initiation of the complement system such as PNH. See Subasinghe, 0003,0008,0170. Accordingly, a person of ordinary skill in the art (POSITA/POSA) would have recognized that the compositions containing compounds of the reference claims may be formulated in oral dosage forms to provide orally administrable compositions of the compounds in the most frequently used dosage forms such as tablets and capsules. The POSA would have desired to provide oral tablets and capsules because they are popularly known as suitable dosage forms for administration of drugs. Further, the artisan would have found it obvious to formulate the compounds in a tablet dosage form because of known advantages such as accuracy of dosage, compactness, portability, blandness of taste or ease of administration. Further given that inhibitors of the complement system can be administered orally, the POSA would have further understood that the reference compounds may be formulated into orally administrable compositions to provide the therapeutic effect of the compounds to inhibit the complement system.
Claims 1, 2, 10-11, and 13-15 and Claims 42, 50-51, and 53-55 (amounts)
Claim 1 further recites comprising about 1 mg to about 1500 mg. Claim 2 limits claim 1, comprising about 1 mg to about 1200 mg, about 1 mg to about 1000 mg, about 1 mg to about 800 mg, about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, or about 1 mg to about 200 mg of the compound or a pharmaceutically acceptable salt. Claim 10 limits claim 1, comprising about 1 mg to about 100 mg of the compound or a pharmaceutically acceptable salt. Claim 11 limits claim 1, comprising about 10 mg or about 30 mg of the compound or a pharmaceutically acceptable salt. Claim 13 limits claim 1, comprising about 100 mg of the compound or a pharmaceutically acceptable salt. Claim 14 limits claim 1, comprising about 200 mg of the compound or a pharmaceutically acceptable salt. Claim 15 limits claim 1, comprising about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg of the compound or a pharmaceutically acceptable salt.
The Subasinghe reference teaches the dosage of inhibitors of complement system will vary with the form of administration (e.g., orally or parenterally – see 0170), the particular compound chosen and the physiological characteristics of the particular patient under treatment. Thus, the POSA would have found it obvious to formulate compositions containing the amounts of the inhibitor for administration at levels already known to be effective for complement system inhibition. The POSA would also have understood it to be routine to adjust the dosage as needed to achieve the desired therapeutic effect, taking into account factors such as route of administration, the specific inhibitor being used, and the patient’s physiological characteristics. According to Subasinghe, generally, small dosages may be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is reached. The therapeutic human dosage, based on physiological studies using rats, may generally range from about 0.01 mg to about 600 mg/kg of body weight per day, and all combinations and subcombinations of ranges therein. Alternatively, the therapeutic human dosage may be from about 0.4 mg to about 10 g or higher, and may be administered in several different dosage units from once to several times a day. See 0169. This range overlaps and encompasses all of the claimed dosage ranges, including an amount as low as 1 mg and as high as 1500 mg, depending on the formulation and patient characteristics. Furthermore, Subasinghe explicitly teaches that the optimal dose will depend on the route of administration, the compound selected, and patient-specific factors, and should be titrated as needed. Such guidance would have led a POSA to systematically explore doses within the tight range through routine experimentation to arrive at a therapeutically effective dose with minimal adverse effects. As such, the specific amounts recited in the claims (e.g., 10 mg, 30 mg, 100 mg, 600 mg, etc.) would have been obvious variations within the range taught by the prior art, and would represent nothing more than optimization of a result effective variable. Therefore, in view of the teachings of Subasinghe regarding the therapeutic application of complement inhibitors their broad dosage range, and guidance on patient-specific adjustments, the claimed amounts would have been obvious to a POSA at the time the invention was filed. The POSA would have sought to formulate the dosage form to provide the desired dosage amount whether administered once or several times a day. These particular teachings meet the claimed dosage limitations for Claims 42, 50-51 and 53-55 which depend from Claim 24 are drawn to a method of treating a disease or condition.
Claimed 21-23 (dosage form)
Claim 21 limits claim 1, wherein the oral dosage form is a capsule. Claim 22 limits claim 1, wherein the oral dosage form is a tablet. Claim 23 limits claim 22. wherein the tablet is a coated tablet. As outlined above, the POSA would have recognized that the compositions of the reference claims may be prepared in orally administrable dosage forms such as capsules and tablets because these are the most commonly used dosage formats. The artisan would have particularly provided a tablet dosage form because of known advantages such as accuracy of dosage, compactness, portability, blandness of taste or ease of administration.
Additionally, since complement inhibitors can be administered orally, the POSA would have reasonably expected that the compounds of the reference claims could be delivered in such a format while preserving therapeutic activity. Regarding the coated tablet limitation, Remington discloses tablets can be made into controlled-release formulas using the hydroxypropylmethylcellulose (HPMC), which functions both to prolong drug release and to act as a film-forming agent in the tablet coating. Accordingly, the POSA would have found it obvious to prepare the active compound in a coated tablet formulated to enable controlled release.
Claims 24, 36, 42, 50-51, 53-55 and 61 (method)
With respect to the method of treating PNH in Claim 24, the reference claims disclose compounds that act as effective inhibitors of the complement system. These inhibitors are described as useful in therapeutic methods for treating or preventing diseases or conditions characterized by aberrant complement system activity, such as paroxysmal nocturnal hemoglobinuria (PNH). See Claims 1 and 5. Subasinghe supports this by teaching that such inhibitors are useful for treating diseases involving undesirable initiation of the complement system, including PNH. Therefore, the POSA would have found it obvious to formulate these compounds for oral administration to therapeutically treat PNH, a condition marked by abnormal or undesirable complement system activation.
Claim 36 limits claim 35, wherein the PNH is characterized by one or more of hemolytic anemia, thrombosis, and impaired bone marrow function. Subasinghe further teaches that, in addition to PNH, the inhibitors can be used to treat hemolytic anemia. Therefore, the POSA would have further found it obvious to treat a subject presenting with both hemolytic anemia and PNH such as the case wherein the PNH is characterized by hemolytic anemia. Given that the complement system inhibitors are useful for treating both conditions, the POSA would have reasonably understood that the inhibitors can be used to treat a subject wherein both conditions are present such as those with PNH characterized by hemolytic anemia.
As indicated above for Claims 2, 10, 11 and 13-15, the particular teachings from Subasinghe meet the claimed dosage limitations for Claims 42, 50-51 and 53-55 which depend from directly or indirectly Claim 24.
Claim 61 limits claim 24, wherein the compound or a pharmaceutically acceptable salt is administered once daily, twice daily, or three times daily. As mentioned above, Subasinghe discloses therapeutic doses may be administered once to several times a day. Therefore, the POSA would have at least found the claimed limitation of once a day to be obvious.
D. Claims 1, 2, 10, 11, 13-15, 21-24, 36, 42, 50-51, 53-55 and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,043,610 (reference claims) in view of Nathan Brown ((2012). Front Matter. In Bioisosteres in Medicinal Chemistry (eds R. Mannhold, H. Kubinyi, G. Folkers and N. Brown). https://doi.org/10.1002/9783527654307.fmatter), Remington (Gennaro, Alfonso. Remington’s pharmaceutical Sciences. Easton, PA:Mack Pub. Co., 1990), and Subasinghe et al. (US 2005/0004031 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the reference claims are drawn to compounds and methods of treating a disease characterized by aberrant complement system activity including PNH by administering similar compounds in pharmaceutical compositions containing them. The instant compound is
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wherein the reference compound is
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. See reference Claims 1 and 5.
The reference claims do not expressly claim the exact compound, an oral dosage form comprising the compound or the administration of the oral dosage form.
With regard to the difference in compounds, the instant structure
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as compared to the reference structure
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differ in two aspects: the instant compound has a fluorine atom in place of a hydrogen on the pyridine ring, and a hydrogen in the place of a methyl on the phenylene ring. However, it is well established in medicinal chemistry that such modifications fall within the principals of bioisosterism. These principals provide the framework for substituting one functional group for another enabling chemist to rationally design novel therapeutic agents through routine replacement of known substituents with commonly used bioisosteres. For example, Brown discloses “[o]ne of the most significant approaches to assist in efficiently navigating the available chemistry space is that of bioisosteric replacement” (see p. 2). Substitutions between fluorine and hydrogen and hydrogen and methyl are textbook examples of monovalent bioisosteric replacements. Specifically, Brown teaches the following classical monovalent bioisosteres where groups in each row are equivalent:
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See p. 7, Table 1.3.
This specifically identifies F, OH, NH, CH3, and H as equivalent classical monovalent bioisosteres, thereby supporting substitutions such as H[Wingdings font/0xE0]F or CH3[Wingdings font/0xE0]H as routine design strategies.
A person of ordinary skill in the art (POSITA/POSA) would have found it obvious to substituted a hydrogen with a fluoride and a methyl with a hydrogen in the reference compound arriving at the current compound because Brown teaches these atoms as classical equivalent monovalent bioisosteres. The artisan would have recognized that such substitutions are routinely employed for rational compound design in drug development.
With regard to oral compositions for oral administration, the reference claims disclose the compounds are administered to a subject to treat a disease characterized by aberrant complement system activity including PNH. See reference Claims 1 and 4-9. Remington teaches drug substances are most frequently administered orally by means of solid dosage forms such as tablets and capsules. See p. 1633. Tablets remain popular as a dosage form because of the advantages afforded both to the manufacturer (e.g., simplicity and economy of preparation, stability and convenience in packaging, shipping and dispensing) and the patient (e.g., accuracy of dosage, compactness, portability, blandness of taste and ease of administration). Additionally, Subasinghe discloses inhibitors of complement system and proteins formed by the system (e.g., C3a and C5a) are suitably orally administered for treating diseases implicated in undesirable initiation of the complement system such as PNH. See Subasinghe, 0003,0008,0170. Accordingly, a person of ordinary skill in the art (POSITA/POSA) would have recognized that the compositions containing compounds of the reference claims may be formulated in oral dosage forms to provide orally administrable compositions of the compounds in the most frequently used dosage forms such as tablets and capsules. The POSA would have desired to provide oral tablets and capsules because they are popularly known as suitable dosage forms for administration of drugs. Further, the artisan would have found it obvious to formulate the compounds in a tablet dosage form because of known advantages such as accuracy of dosage, compactness, portability, blandness of taste or ease of administration. Further given that inhibitors of the complement system can be administered orally, the POSA would have further understood that the reference compounds may be formulated into orally administrable compositions to provide the therapeutic effect of the compounds to inhibit the complement system.
Claims 1, 2, 10-11, and 13-15 and Claims 42, 50-51, and 53-55 (amounts)
Claim 1 further recites comprising about 1 mg to about 1500 mg. Claim 2 limits claim 1, comprising about 1 mg to about 1200 mg, about 1 mg to about 1000 mg, about 1 mg to about 800 mg, about 1 mg to about 600 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, or about 1 mg to about 200 mg of the compound or a pharmaceutically acceptable salt. Claim 10 limits claim 1, comprising about 1 mg to about 100 mg of the compound or a pharmaceutically acceptable salt. Claim 11 limits claim 1, comprising about 10 mg or about 30 mg of the compound or a pharmaceutically acceptable salt. Claim 13 limits claim 1, comprising about 100 mg of the compound or a pharmaceutically acceptable salt. Claim 14 limits claim 1, comprising about 200 mg of the compound or a pharmaceutically acceptable salt. Claim 15 limits claim 1, comprising about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg of the compound or a pharmaceutically acceptable salt.
The Subasinghe reference teaches the dosage of inhibitors of complement system will vary with the form of administration (e.g., orally or parenterally – see 0170), the particular compound chosen and the physiological characteristics of the particular patient under treatment. Thus, the POSA would have found it obvious to formulate compositions containing the amounts of the inhibitor for administration at levels already known to be effective for complement system inhibition. The POSA would also have understood it to be routine to adjust the dosage as needed to achieve the desired therapeutic effect, taking into account factors such as route of administration, the specific inhibitor being used, and the patient’s physiological characteristics. According to Subasinghe, generally, small dosages may be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is reached. The therapeutic human dosage, based on physiological studies using rats, may generally range from about 0.01 mg to about 600 mg/kg of body weight per day, and all combinations and subcombinations of ranges therein. Alternatively, the therapeutic human dosage may be from about 0.4 mg to about 10 g or higher, and may be administered in several different dosage units from once to several times a day. See 0169. This range overlaps and encompasses all of the claimed dosage ranges, including an amount as low as 1 mg and as high as 1500 mg, depending on the formulation and patient characteristics. Furthermore, Subasinghe explicitly teaches that the optimal dose will depend on the route of administration, the compound selected, and patient-specific factors, and should be titrated as needed. Such guidance would have led a POSA to systematically explore doses within the tight range through routine experimentation to arrive at a therapeutically effective dose with minimal adverse effects. As such, the specific amounts recited in the claims (e.g., 10 mg, 30 mg, 100 mg, 600 mg, etc.) would have been obvious variations within the range taught by the prior art, and would represent nothing more than optimization of a result effective variable. Therefore, in view of the teachings of Subasinghe regarding the therapeutic application of complement inhibitors their broad dosage range, and guidance on patient-specific adjustments, the claimed amounts would have been obvious to a POSA at the time the invention was filed. The POSA would have sought to formulate the dosage form to provide the desired dosage amount whether administered once or several times a day. These particular teachings meet the claimed dosage limitations for Claims 42, 50-51 and 53-55 which depend from Claim 24 are drawn to a method of treating a disease or condition.
Claimed 21-23 (dosage form)
Claim 21 limits claim 1, wherein the oral dosage form is a capsule. Claim 22 limits claim 1, wherein the oral dosage form is a tablet. Claim 23 limits claim 22. wherein the tablet is a coated tablet. As outlined above, the POSA would have recognized that the compositions of the reference claims may be prepared in orally administrable dosage forms such as capsules and tablets because these are the most commonly used dosage formats. The artisan would have particularly provided a tablet dosage form because of known advantages such as accuracy of dosage, compactness, portability, blandness of taste or ease of administration.
Additionally, since complement inhibitors can be administered orally, the POSA would have reasonably expected that the compounds of the reference claims could be delivered in such a format while preserving therapeutic activity. Regarding the coated tablet limitation, Remington discloses tablets can be made into controlled-release formulas using the hydroxypropylmethylcellulose (HPMC), which functions both to prolong drug release and to act as a film-forming agent in the tablet coating. Accordingly, the POSA would have found it obvious to prepare the active compound in a coated tablet formulated to enable controlled release.
Claims 24, 36, 42, 50-51, 53-55 and 61 (method)
With respect to the method of treating PNH in Claim 24, the reference claims disclose compounds that act as effective inhibitors of the complement system. These inhibitors are described as useful in therapeutic methods for treating or preventing diseases or conditions characterized by aberrant complement system activity, such as paroxysmal nocturnal hemoglobinuria (PNH). See Claims 1 and 5. Subasinghe supports this by teaching that such inhibitors are useful for treating diseases involving undesirable initiation of the complement system, including PNH. Therefore, the POSA would have found it obvious to formulate these compounds for oral administration to therapeutically treat PNH, a condition marked by abnormal or undesirable complement system activation.
Claim 36 limits claim 35, wherein the PNH is characterized by one or more of hemolytic anemia, thrombosis, and impaired bone marrow function. Subasinghe further teaches that, in addition to PNH, the inhibitors can be used to treat hemolytic anemia. Therefore, the POSA would have further found it obvious to treat a subject presenting with both hemolytic anemia and PNH such as the case wherein the PNH is characterized by hemolytic anemia. Given that the complement system inhibitors are useful for treating both conditions, the POSA would have reasonably understood that the inhibitors can be used to treat a subject wherein both conditions are present such as those with PNH characterized by hemolytic anemia.
As indicated above for Claims 2, 10, 11 and 13-15, the particular teachings from Subasinghe meet the claimed dosage limitations for Claims 42, 50-51 and 53-55 which depend from directly or indirectly Claim 24.
Claim 61 limits claim 24, wherein the compound or a pharmaceutically acceptable salt is administered once daily, twice daily, or three times daily. As mentioned above, Subasinghe discloses therapeutic doses may be administered once to several times a day. Therefore, the POSA would have at least found the claimed limitation of once a day to be obvious.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622