DETAILED ACTION
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 Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 08/29/2025, in which claims 1-65 are canceled and claims 66-100 are newly added.
Claims 66-100 are pending and are examined on the merits herein.
Applicant’s declaration of Smith, filed on 08/29/2025, is acknowledged and further discussed below.
Priority
The instant application is a 371 of PCT/GB2020/051439 filed on 06/15/2020, which claims domestic benefit to 62/861,725 filed on 06/14/2019 and foreign priority to United Kingdom 1910116.1 filed on 07/15/2019.
Information Disclosure Statement
The information disclosure statements (IDS) dated 06/26/2025, 08/14/2025, and 08/29/2025 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statements have been considered by the examiner.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 1, 4-5, 11, 25, 27-50, and 54-65 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton in view of Valerieva has been fully considered and is persuasive, as claims 1, 4-5, 11, 25, 27-50, and 54-65 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 6-10, 12, and 51-53 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton and Valerieva in view of Magerl has been fully considered and is persuasive, as claims 6-10, 12, and 51-53 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Beaton and Valerieva in view of Trinius has been fully considered and is persuasive, as claim 26 is canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 1, 4-5, 11 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-32 and 34 of U.S. Patent No. 11,234,939 B2, further in view of Valerieva has been fully considered and is persuasive, as claims 1, 4-5, 11 and 25 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 6-10, 12, and 51-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-32 and 34 of U.S. Patent No. 11,234,939 B2, further in view of Valerieva as applied to claims 1 and 4 further in view of Magerl has been fully considered and is persuasive, as claims 6-10, 12, and 51-53 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 27-50 and 54-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-32, and 34 of U.S. Patent No. 11,234,939 B2, further in view of Valerieva as applied to claim 1, further in view of Magerl has been fully considered and is persuasive, as claims 27-50 and 54-65 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claim 26 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-32, and 34 of U.S. Patent No. 11,234,939 B2 in view of Valerieva as applied to claims 1 and 25, further in view of Trinius has been fully considered and is persuasive, as claim 26 is canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 1, 4-12, 25-26, 31-32, 40-41, and 51-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of copending Application No. 18/264,810 has been fully considered and is persuasive, as claims 1, 4-12, 25-26, 31-32, 40-41, and 51-65 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 27-30, 33-39, and 42-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of copending Application No. 18/264,810 as applied to claim 1 in view of Beaton has been fully considered and is persuasive, as 27-30, 33-39, and 42-50 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 1, 4-12, 25-26, and 51-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 46-47, and 52-84 of copending Application No. 18/249,076 has been fully considered and is persuasive, as claims 1, 4-12, 25-26, and 51-53 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 08/29/2025, with respect that claims 27-30, 33-39, and 42-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of copending Application No. 18/264,810 as applied to claim 1 in view of Beaton has been fully considered and is persuasive, as 27-30, 33-39, and 42-50 are canceled. This rejection has been withdrawn.
The following are new grounds of rejection necessitated by Applicant’s amendment, in which claim 66 recites orally administering 600 mg.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 66-67, 73, 78-86, 88-95, and 97-100 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 Al; IDS 09/09/2022) in view of Valerieva et al. (Alergia Astma Immunologia, 2018; PTO-892 10/10/2024).
Beaton teaches that inhibitors of plasma kallikrein have a number of therapeutic applications, including the treatment of hereditary angioedema (HAE) (page 1, lines 8-10). Beaton teaches that plasma kallikrein inhibitors reduce the positive feedback amplification of the kallikrein system by the contact activation system through inhibiting activation of factor XII (page 3, lines 18-22). Beaton teaches the compound of formula A (page 10, line 5) as a small molecule plasma kallikrein inhibitor for the treatment of HAE (claim 19). Beaton teaches that the compound may be formulated with a pharmaceutically acceptable adjuvant, diluent or carrier (claim 13), and that the compound may be administered orally (page 27, lines 5-20). Beaton discloses an oral administration at a dosage of 10 mg/kg of Formula A to a subject such that the Cmax is 1942 ng/mL, which indicates a plasma concentration of 1942 ng/mL, which is greater than 500 ng/mL (example 27 on page 62, lines 5-20). Beaton teaches that the compound will be administered as a formulation in association with one or more pharmaceutically acceptable excipients (page 25, lines 29-30) and may be administered systemically by oral administration in the form of, among others, tablets (paragraph bridging pages 26-27).
Beaton does not expressly teach that a compound of formula A is administered on-demand.
Valerieva discusses the state of the art in treating hereditary angioedema. In particular, effective and safe treatments for the most common form of genetic defect leading to hereditary angioedema are available and new drugs are under investigation both for the on-demand therapy and for the prophylaxis of the attacks. Valerieva states that acute treatments have been proved to reduce severity and duration of the attack and are on demand therapy (page 175, paragraph 1). Valerieva teaches that a symptom of an HAE attack is abdominal pain (page 177, paragraph 1). Valerieva discusses several currently used acute treatments of hereditary angioedema, including for example, Icatibant, which is delivered as prefilled syringe to be administered subcutaneously at a fixed dose of 30 mg, and plasma-derived C1-INH (pdC1-INH), which is delivered in vials of 500 IU for a weight-based dose of 20 IU/Kg (page 177, paragraph 6).
Valerieva teaches that there is a treatment burden associated with any intravenously administered medication. Often, patients are unable or unwilling to access their veins for drug administration. Patients with venous access problems used subcutaneous ports, which are associated with risks of infection and thrombosis. Development of a safe and effective oral therapy would meet the major unmet need in terms of ease of treatment administration (page 179, paragraph 1). Valerieva also teaches that all currently available prophylactic agents are associated with breakthrough attacks; therefore, an acute treatment plan is essential for every patient, irrespectively to the presence of prophylactic treatment (page 177, paragraph 5).
Valerieva teaches that orally available small molecule inhibitors of plasma kallikrein (PK) are under investigation for the treatment of acute HAE attacks (page 177, paragraphs 8-9 and Table I). BCX7353 is one such treatment. It is a novel oral plasma kallikrein inhibitor with promising results showing that a single 750 mg oral dose was well tolerated and superior to placebo for the treatment of acute attacks in HAE patients (page 177, paragraph 8). KVD900 - which is a small molecule that is a selective and orally available PK inhibitor- also modulates the inhibition of plasma kallikrein and is another treatment under investigation in a Phase I trial for acute AE attacks (page 177, paragraph 9).
Because Valerieva teaches that acute treatment reduces severity and duration of attack and teaches that prophylactic and acute treatments are the two different types of treatment for HAE, it suggests that acute treatments are the treatments that are given in response to symptoms of an ongoing attack. Furthermore, the instant specification defines “on-demand” treatment by stating “The skilled person would understand "on-demand" treatment, in the context of HAE, to mean that the compound of Formula A is administered upon need of therapy in connection with one specific acute HAE attack” (instant specification page 7, lines 30-32). A person of ordinary skill in the art would have been motivated to apply the HAE treatment of Beaton for on-demand therapy of acute HAE attacks, because Valerieva teaches that oral treatment would meet the major unmet need in terms of ease of treatment administration and that an acute treatment plan is essential for every patient, and that acute treatments have been proved to reduce severity and duration of the attack and are on demand therapy. One of ordinary skill in the art would have a reasonable expectation of success in administering the treatment of Beaton on-demand because Beaton teaches the compound Formula A, which is the instantly recited compound, that is an orally available small molecule inhibitor of plasma kallikrein useful for treating HAE, and Valerieva teaches that oral plasma kallikrein inhibitors are known in the art to show promising results as on-demand treatment for acute HAE attacks.
Alternatively, it would have been obvious to try administering formula A as an on-demand treatment for HAE because Beaton teaches that formula A is useful for treating HAE and Valerieva teaches that HAE is treated either prophylactically or as a response to an acute attack.
Furthermore, Beaton teaches that formula A would be administered in a daily dose of 10 mg to 1000 mg (page 26, line 14), and that the compound may be administered in single or divided doses (page 27, line 19). Beaton teaches that the dosages are based on an average human subject having a weight of about 60kg to 70 kg and that the physician will readily be able to determine doses for subjects whose weight falls outside this range (page 26, lines 20-22). Beaton also discloses pharmacokinetic studies in an animal model using a single oral dosage of 10 mg/kg (page 62, lines 6-10). It would have been prima facie obvious for one of ordinary skill in the art to begin optimization of the dosage of formula A with a 600 mg dosage for a 60 kg patient because Beaton suggests a dosage of 10 mg/kg. Furthermore, MPEP 2144.05(II)(A) states that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Thus it would have been prima facie obvious for one of ordinary still in the art to optimize the dosages of formula A within the range of 10-1000 mg, including the timing of divided daily dosages. One of ordinary skill in the art would have a reasonable expectation of success because teaches that formula A would be administered in a daily dose of 10 mg to 1000 mg in a single or divided dose and that the physician will readily be able to determine doses for subjects.
Regarding claim 80, Beaton teaches that plasma kallikrein plays a role in a number of inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients with a genetic deficiency in C1 esterase inhibitor suffer from HAE (page 1, lines 27-30). Administering plasma kallikrein inhibitors reduces the positive feedback amplification of the kallikrein system by the contact activation system through inhibiting activation of factor XII (page 3, lines 18-22).
As the teachings of the prior art disclose the administration of the formula A of Beaton, which is the same drug as that of the instant claims, to the same patient population (HAE patients), and it would be obvious to do so at the same dosage of 600 mg, the results recited in instant claim 80 would necessarily flow, thereby meeting the instant claim limitations. One of ordinary skill in the art would have a reasonable expectation of success in blocking activation of the contact system for up to six hours because Beaton teaches that formula A is a plasma kallikrein inhibitor useful for the treatment of HAE and that plasma kallikrein inhibitors inhibit activation of factor XXII and thereby reduce amplification of the kallikrein system by the contact system.
Claims 68-72 and 74-77 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 Al; IDS 09/09/2022) in view of Valerieva et al. (Alergia Astma Immunologia, 2018; PTO-892 10/10/2024) as applied to claim 66, further in view of Magerl et al. (Clinical and Experimental Dermatology, 2014; IDS 09/09/2022).
The combined teachings of Beaton and Valerieva are as above. Furthermore, Valerieva teaches that swelling in HAE attacks is caused by contact system activation and local release of bradykinin (page 176, paragraph 2) and that KVD 900 treats HAE attacks by inhibiting PK (page 177, paragraph 9). Valerieva teaches that swelling in HAE attacks is caused by activation of the contact system and suggests orally administered PK inhibitors for the on-demand treatment of HAE attacks. Beaton teaches that the compound of formula A blocks contact system activation in HAE (page 3, lines 18-22).
The combined teachings of Beaton and Valerieva do not expressly teach the treatment of HAE within 1 hour of the symptom of an acute HAE attack being recognized (claims 6-7, and 51-53) or treatment in the prodromal phase (claims 8-10) while preventing progression to the swelling stage of an acute HAE attack (claim 12).
Magerl suggests that prodromes can be used as an indication for treatment in HAE patients due to the high certainty of the patients in predicting attacks based on prodromes, and also teaches that early treatment is more effective (paragraph bridging 301-302). Magerl teaches that prodromes develop minutes to hours before the onset of the actual HAE episode (page 299, paragraph 2) with some patients experiencing the first prodromal symptom less than an hour before the HAE attack (Figure 4 on page 300). Thus Magerl teaches and suggests treatment within minutes of a prodrome of an acute HAE attack being recognized. An example of a prodrome includes erythema marginatum (page 301, paragraph 6).
A person of ordinary skill in the art before the effective filing date of the invention would have had a reasonable expectation of success in halting the progress of a HAE attack before the swelling stage by treating the HAE patient upon recognition of a prodromal symptom. One of ordinary skill in the art would have been motivated to administer Formula A to a patient experiencing a prodrome of an acute HAE attack because Magerl teaches that early administration of treatment is better for patients. A person of ordinary skill in the art before the effective filing date of the invention would have a reasonable expectation of success in treating an HAE attack by dosing the compound of Beaton on demand, as suggested by Valerieva, upon recognition of a prodromal symptom of an acute HAE attack, as taught by Magerl because the combined teachings of Beaton and Valerieva suggest the treatment of HAE attacks using Formula A and Magerl teaches that patients are known to predict attacks based on prodromes and that prodromes could be used as an indication for treatment in some patients.
Claims 87 and 96 are rejected under 35 U.S.C. 103 as being unpatentable over Beaton et al. (WO 2017/208005 Al; IDS 09/09/2022) further in view of Valerieva et al. (Alergia Astma Immunologia, 2018; PTO-892 10/10/2024) as applied to claims 66 and 82-83, 85, and 94-95 further in view of Trinius (EP2815749A1; PTO-892).
The combined teachings of Beaton and Valerieva are as above.
The combined teachings of Beaton and Valerieva does not teach formulation wherein the oral dosage form is a tablet comprising microcrystalline cellulose, croscarmellose sodium, and polyvinyl pyrrolidone.
Trinius teaches compositions of small molecules including for example 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (abstract and [0008]) and teaches that the compositions that may be used to treat hereditary angioedema among other conditions (page 120, lines 16-23). The compositions may be in oral dosage forms (page 76, lines 17-20). The compositions may comprise a binder, which may be selected from a list including polyvinyl pyrrolidone (page 76, lines 37-38). The compositions may comprise a disintegrant, selected from a list including croscarmellose sodium (page 76, line 58 to page 77, line 1). The compositions may comprise additional components selected from a list including micro-crystalline cellulose (page 76, lines 24-27).
It would have been prima facie obvious to combine the teachings of Beaton, Valerieva, and Trinius before the effective filing date of the claimed invention by formulating the compound of Formula A in a composition comprising microcrystalline cellulose, croscarmellose sodium, and polyvinyl pyrrolidone to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select the excipients of Trinius for the formulation of Formula A because Trinius teaches oral formulation of small molecules that may be used to treat hereditary angioedema.
Response to Arguments
Applicant's arguments and the declaration of Smith filed 08/29/2025 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that a long-felt need has existed for an oral, on-demand treatment of acute HAE attacks, and that the claimed invention satisfies this long-felt need (Remarks, page 9, paragraph 1). This is not persuasive.
In order to establish long-felt need, Applicant must establish that the need has been a persistent one that was recognized by those of ordinary skill in the art (MPEP 716.04). However, Applicant has failed to demonstrate that an oral on-demand treatment for acute HAE attacks was recognized by those of ordinary skill in the art as a persistent need. As discussed in the grounds of rejection above, Valerieva demonstrates that acute treatments with other routes of administration were in use as on-demand therapy to reduce severity and duration of the HAE attack. Although an orally administered on demand treatment for HAE was not available prior to the filing date of the claimed invention, Applicant has not established that a specifically oral route of on-demand treatment was recognized in the art as being necessary, as other routes of administration were available for the treatment of HAE. Thus, Applicant has not submitted evidence to satisfy the requirement of a long-felt need.
Applicant argues that the evidence of record is sufficient to establish that no person of ordinary skill in the art would have reasonably expected that orally administered sebetralstat (Formula A) would have been successful for the on-demand treatment of an HAE attack (Remarks, page 8, paragraph 4). In particular, Applicant argues that Valerieva fails to provide a person of ordinary skill in the art with a reasonable expectation that sebetralstat would have been successful as an oral, on-demand treatment for HAE attacks based on the Smith Declaration because understanding the human pharmacokinetic-pharmacodynamic (PK-PD) profile of a drug is critical to being able to predict, with any reasonable degree of certainty, whether that drug would be successful in treating an HAE attack on-demand (Remarks, page 10, paragraph 2). Applicant also emphasizes that the instant application provides, for the first time, human PK and PD data showing that sebetralstat rapidly suppresses plasma kallikrein activity after oral administration (Smith declaration, page 7, paragraph 4). This is not persuasive.
Valerieva suggests oral administration as a strategy for treating HAE attacks and teaches that small molecules that are PK inhibitors are under investigation for this treatment route. Beaton teaches that the compound of formula A is a small molecule PK inhibitor and is suitable for oral administration. One of ordinary skill in the art would have been motivated to investigate the oral administration of Formula A for the treatment of acute attacks because Valerieva teaches that oral treatment would meet the major unmet need in terms of ease of treatment administration and that an acute treatment plan is essential for every patient. Valerieva further teaches that oral acute treatments were being investigated, which suggests that one of ordinary skill in the art would have tested a compound to see if it is suitable as an oral acute treatment of HAE. Furthermore, PK-PD is standard data to obtain in the pharmaceutical art, and one of ordinary skill in the art would have obtained this data in the development of the oral administration of Formula A with the understanding that PK-PD data is dependent on formulation. Formula A is known to orally treat HAE by the same pathway of targeting PK inhibition as that of other known oral acute attack treatments which were being investigated, and methods of testing the usefulness of an oral treatment of acute HAE attacks were also known. Thus it would have been obvious for one of ordinary skill in the art to apply Formula A to this treatment method.
Applicant further argues that one of ordinary skill in the art would not have had a reasonable expectation of success because there were no FDA-approved oral, on-demand treatments for HAE. Applicant cites the labeling of BCX7353 upon its approval by the FDA in 2020 saying that the treatment is not for use in acute HAE attacks (Smith Declaration, page 6, paragraph 1). Applicant further cites clinical trial information discontinuing trials of acute HAE treatment using BCX7353. This is not persuasive. Applicant’s references regarding BCX7353, which is a different compound from that of the instantly claimed invention, date from after the effective filing date of the claimed invention and thus would not have been available for consideration by one of ordinary skill in the art before the effective filing date of the claimed invention. The website cited by the Applicant showing the results of the clinical trial of BCX7353 indicates that the results for the study were first submitted on 2020-11-17 (Study of BCX7353 as a Treatment for Attacks of Hereditary Angioedema, page 4, accessed 05/15/2025, PTO-892). Thus, these data were not available at the effective filing date of the claimed invention and were not available until 2020. If this reference was intended to show a lack of reasonable expectation of success, this argument is not persuasive because there is no indication as to why clinical trials of BCX7353 for acute treatment of HAE were discontinued.
Applicant does not provide a citation from Valerieva and so it is not demonstrated that Valerieva evidences that others have tried, but have failed, to use a small molecule plasma kallikrein inhibitor as an oral, on-demand HAE treatment. To the contrary, Valerieva teaches that two treatments BCX7353 and KVD900 were under investigation for treatment of acute HAE attacks and the BCX7353 shows promising results in a clinical trial. Additionally, because BCX7353 is not the same compound as formula A of the instant claims it cannot provide evidence of teaching away as a post-dated reference.
Thus, Valerieva suggests the suitability of the orally available small molecule inhibitor of plasma kallikrein of Beaton for acute administration and the instant claims are rendered obvious over the prior art.
Because Applicant’s arguments are not persuasive, the instant claims are rendered obvious over the prior art.
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 66-67, 73, 78-86, 88-95, and 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-35 of U.S. Patent No. 11,234,939 B2, further in view of Valerieva et al. (Alergia Astma Immunologia, 2018; PTO-892 10/10/2024)and Beaton et al. (WO 2017/208005 Al; IDS 09/09/2022). Although the claims at issue are not identical, they are not patentably distinct from each other.
‘939 is drawn to an oral solid dosage form of the compound of Formula A (claim 1), which is the same compound as that of instant claim 1. Claim 2 further limits the oral solid dosage to 0.1-1,000 mg. ‘939 is further drawn to a method treating a disease or condition mediated by plasma kallikrein comprising administering the compound of claim 1 (claim 30). Claim 34 further limits the method to the treatment of hereditary angioedema.
The claims of ‘939 differ from that of the claimed invention in that ‘939 does not expressly claim that a compound of formula A is administered on-demand upon recognition of a symptom of the attack to reduce the duration of the attack, nor does ‘939 claim the pathway of the PK inhibitor or the dosages of Formula A. Beaton teaches that inhibitors of plasma kallikrein have a number of therapeutic applications, including the treatment of hereditary angioedema (HAE) (page 1, lines 8-10). Beaton teaches that plasma kallikrein inhibitors reduce the positive feedback amplification of the kallikrein system by the contact activation system through inhibiting activation of factor XII (page 3, lines 18-22). Beaton teaches the compound of formula A (page 10, line 5) as a small molecule plasma kallikrein inhibitor for the treatment of HAE (claim 19). Beaton teaches that the compound may be formulated with a pharmaceutically acceptable adjuvant, diluent or carrier (claim 13), and that the compound may be administered orally (page 27, lines 5-20). Beaton discloses an oral administration at a dosage of 10 mg/kg of Formula A to a subject such that the Cmax is 1942 ng/mL, which indicates a plasma concentration of 1942 ng/mL, which is greater than 500 ng/mL (example 27 on page 62, lines 5-20).
Valerieva teaches that orally available small molecule inhibitors of plasma kallikrein (PK) are used for the treatment of acute HAE attacks (page 177, paragraph 10 and Table I); it is therefore dosed in response to symptoms of an ongoing attack. Valerieva teaches that a symptom of an HAE attack is abdominal pain (page 177, paragraph 1). Valerieva teaches that acute treatments reduce the severity and duration of the attack and are on demand therapy (page 175, paragraph 1).
A person of ordinary skill in the art would have a reasonable expectation of success in applying the HAE treatment of ‘939 for prophylactic and acute therapy in HAE as taught by Valerieva. It would be obvious to apply the known PK inhibitor of ‘939 in the known techniques of prophylactic and acute therapy in HAE of Valerieva to arrive at a method for treating HAE that allows ease of treatment administration and patient-tailored treatment. Furthermore, a person of ordinary skill in the art would have been motivated to apply the HAE treatment of ‘939 for acute therapy of HAE, because Valerieva teaches that oral treatment would meet the major unmet need in terms of ease of treatment administration and that an acute treatment plan is essential for every patient. One of ordinary skill in the art would have a reasonable expectation of success because ‘939 teaches a compound that is an orally available small molecule inhibitor of plasma kallikrein, and Valerieva teaches that oral plasma kallikrein inhibitors are known in the art to show promising results for treating HAE attacks.
Furthermore, it would have been prima facie obvious to combine the claims of ‘939 with the teachings of Beaton and Valerieva before the effective filing date of the claimed invention by administering the compound of formula A of ‘939 according to the treatment regimens of Beaton to arrive at the instantly claimed invention. A person of ordinary skill in the art would have been motivated to administer the compound of formula A of ‘939 according to the treatment regimens of Beaton because Beaton teaches the same compound for the same purpose of treating HAE.
In addition, Beaton teaches that formula A would be administered in a daily dose of 10 mg to 1000 mg (page 26, line 14), and that the compound may be administered in single or divided doses (page 27, line 19). Beaton teaches that the dosages are based on an average human subject having a weight of about 60kg to 70kg and that the physician will readily be able to determine doses for subjects whose weight falls outside this range (page 26, lines 20-22). Beaton also discloses pharmacokinetic studies in an animal model using a single oral dosage of 10 mg/kg (page 62, lines 6-10). It would have been prima facie obvious for one of ordinary skill in the art to begin optimization of the dosage of formula A with a 600mg dosage for a 60kg patient because Beaton suggests a dosage of 10 mg/kg. Furthermore, MPEP 2144.05(II)(A) states that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Thus it would have been prima facie obvious for one of ordinary still in the art to optimize the dosages of formula A within the range of 10-1000 mg, including the timing of divided daily dosages. One of ordinary skill in the art would have a reasonable expectation of success because teaches that formula A would be administered in a daily dose of 10 mg to 1000 mg in a single or divided dose and that the physician will readily be able to determine doses for subjects.
Regarding instant claim 80, Beaton teaches that plasma kallikrein plays a role in a number of inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients with a genetic deficiency in C1 esterase inhibitor suffer from HAE (page 1, lines 27-30). Administering plasma kallikrein inhibitors reduces the positive feedback amplification of the kallikrein system by the contact activation system through inhibiting activation of factor XII (page 3, lines 18-22). As the teachings of the prior art disclose the administration of the formula A of Beaton, which is the same drug as that of the instant claims, to the same patient population (HAE patients), and it would be obvious to do so at the same dosage of 600 mg, the results recited in instant claim 80 would necessarily flow, thereby meeting the instant claim limitations. One of ordinary skill in the art would have a reasonable expectation of success in blocking activation of the contact system for up to six hours because Beaton teaches that formula A is a plasma kallikrein inhibitor useful for the treatment of HAE and that plasma kallikrein inhibitors inhibit activation of factor XXII and thereby reduce amplification of the kallikrein system by the contact system.
Claims 68-72 and 74-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-32, and 34 of U.S. Patent No. 11,234,939 B2, further in view of Valerieva et al. (Alergia Astma Immunologia, 2018; PTO-892 10/10/2024) and Beaton et al. (WO 2017/208005 Al; IDS 09/09/2022) as applied to claim 66, further in view of Magerl et al. (Clinical and Experimental Dermatology, 2014; IDS 09/09/2022). Although the claims at issue are not identical, they are not patentably distinct from each other.
‘939 claims as above. Furthermore, Valerieva teaches that swelling in HAE attacks is caused by contact system activation and local release of bradykinin (page 176, paragraph 2) and that KVD900 treats HAE attacks by inhibiting PK (page 177, paragraph 9).
The claims of ‘939 differ from that of the claimed invention in that ‘939 in does not claim the treatment of HAE within 1 hour of the symptom of an acute HAE attack being recognized or treatment in the prodromal phase while preventing progression to the swelling stage of an acute HAE attack.
Magerl teaches that prodromes develop minutes to hours before the onset of the actual HAE episode (page 299, paragraph 2) with some patients experiencing the first prodromal symptom less than an hour before the HAE attack (Figure 4 on page 300), and that prodromes could be used as an indication for treatment in some patients as early treatment is more effective (paragraph bridging 301-302). Thus Magerl teaches and suggests treatment within minutes of a prodrome of an acute HAE attack being recognized. Magerl teaches that an example of a prodrome includes erythema marginatum (page 301, paragraph 6).
A person of ordinary skill in the art before the effective filing date of the invention would have a reasonable expectation of success in treating an HAE attack by dosing the compound of ‘939 on demand, as taught by Valerieva, upon recognition of a prodromal symptom of an acute HAE attack, as taught by Magerl. It would be obvious to begin treatment at the recognition of a prodromal symptom to improve the efficacy of the treatment of HAE.
Regarding claim 77, Valerieva teaches that swelling in HAE attacks is caused by activation of the contact system and suggests orally administered PK inhibitors for the on-demand treatment of HAE attacks. ‘939 claims that the compound of formula A blocks contact system activation in HAE (page 3, lines 18-22). A person of ordinary skill in the art before the effective filing date of the invention would have a reasonable expectation of success in halting the progress of a HAE attack before the swelling stage, as taught by Valerieva in view of ‘939, by treating that HAE patient upon recognition of a prodromal symptom, as taught by Magerl. It would have been obvious to improve the known method of treating HAE with Formula A by administering Formula A upon recognition of a prodromal symptom in order to prevent swelling and decrease the severity and duration of the HAE attack.
Claims 87 and 96 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-32, and 34 of U.S. Patent No. 11,234,939 B2, further in view of Valerieva et al. (Alergia Astma Immunologia, 2018; PTO-892 10/10/2024) and Beaton et al. (WO 2017/208005 Al; IDS 09/09/2022), as applied to claims 66, 83, 89, and 94-95, further in view of Trinius (EP2815749A1; PTO-892).
‘939 claims as above. Furthermore, claim 7 further limits the dosage form to include a diluent selected from a list including microcrystalline cellulose. Claim 9 further limits the composition of claim 1 further comprising further comprising a disintegrant, lubricant, and/or glidant, and claim 4 further limits the composition comprising a binder.
The claims of ‘939 differ from that of the claimed invention in that ‘939 does not claim the formulation wherein the oral dosage form is a tablet comprising microcrystalline cellulose, croscarmellose sodium and polyvinyl pyrrolidone.
Trinius teaches compositions of small molecules including for example 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (abstract and [0008]) and teaches that the compositions that may be used to treat hereditary angioedema among other conditions (page 120, lines 16-23). The compositions may be in oral dosage forms (page 76, lines 17-20). The compositions may comprise a binder, which may be selected from a list including polyvinyl pyrrolidone (page 76, lines 37-38). The compositions may comprise a disintegrant, selected from a list including croscarmellose sodium (page 76, line 58 to page 77, line 1).
It would have been prima facie obvious to combine the claims of ‘939 with the teachings Trinius before the effective filing date of the claimed invention by formulating the compound of Formula A in a composition comprising microcrystalline cellulose, croscarmellose sodium, and polyvinyl pyrrolidone to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select the excipients of Trinius the formulation of Formula A because Trinius teaches oral formulation of small molecules that may be used to treat hereditary angioedema and ‘939 claims the composition further comprising a binder and disintegrant.
Claims 66-77, 81-83, 87-89, 94-96, and 100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of copending Application No. 18/264,810 (reference application; claims filed 9 Aug 2023). Although the claims at issue are not identical, they are not patentably distinct from each other.
‘810 claim 1 recites a method for treating HAE on-demand comprising orally administering the compound of Formula A to a patient in need thereof on-demand wherein the administration of Formula A reduces the need for a second treatment of the HAE attack within 4 hours of taking the compound of Formula A. ‘810 claims 27-28 further limit that the compound is orally administered on-demand upon recognition of a symptom of an acute HAE attack, which includes abdominal pain. ‘810 claim 30 further limits that the compound is orally administered within 5 minutes of the symptom of the HAE attack being recognized. ‘810 claims 31 further limits that the compound is orally administered during the prodromal phase of the HAE attack being recognized, and claim 33 further limits that the compound is administration upon recognition of the prodromal symptom erythema marginatum. The treatment upon recognition of a prodromal symptom is interpreted as indicating that the method prevents progression to the swelling stage of the attack as recited in instant claim 12. ‘810 claim 34 further limits that the method shortens the duration of the HAE attack. ‘810 claims 35 further limit the method to administration of an oral dosage formulation comprising an excipient, and claim 36 further limits the excipients to including with microcrystalline cellulose as a diluent, croscarmellose sodium as a disintegrant, and polyvinyl pyrrolidone as a binder. ‘810 claims 37 further limit the method to administration of 600 mg of the compound of formula A, and claim 38 limits the administration to two tablets each comprising about 300 mg of the compound of formula A.
Although the claims of ‘810 require that the administration of Formula A reduces the need for a second treatment of the HAE attack within 4 hours of taking the compound of Formula A and are thus not identical to the instant claims, they are not patentably distinct from the instant claims because they are drawn to oral administration of Formula A on-demand to a patient for treatment of an HAE attack and thus teach a method of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 78-80, 84-86, 90-93, and 97-99 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of copending Application No. 18/264,810 (reference application; claims filed 9 Aug 2023) as applied to claim 66, in view of Beaton et al. (WO 2017/208005 Al; IDS 09/09/2022).
‘810 claims as above.
The claims of ‘810 differ from that of the claimed invention in that ‘810 does not claim the pathway as a PK inhibitor or the dosages of Formula A in instant claims.
Beaton teaches that inhibitors of plasma kallikrein have a number of therapeutic applications, including the treatment of hereditary angioedema (HAE) (page 1, lines 8-10). Beaton teaches that plasma kallikrein inhibitors reduce the positive feedback amplification of the kallikrein system by the contact activation system through inhibiting activation of factor XII (page 3, lines 18-22). Beaton teaches the compound of formula A (page 10, line 5) as a small molecule plasma kallikrein inhibitor for the treatment of HAE (claim 19). Beaton teaches that the compound may be formulated with a pharmaceutically acceptable adjuvant, diluent or carrier (claim 13), and that the compound may be administered orally (page 27, lines 5-20). Beaton discloses an oral administration at a dosage of 10 mg/kg of Formula A to a subject such that the Cmax is 1942 ng/mL, which indicates a plasma concentration of 1942 ng/mL, which is greater than 500 ng/mL (example 27 on page 62, lines 5-20).
It would have been prima facie obvious to combine the claims of ‘810 with the teachings of Beaton before the effective filing date of the claimed invention by administering the compound of formula A of ‘810 according to the treatment regimens of Beaton to arrive at the instantly claimed invention. A person of ordinary skill in the art would have been motivated to administer the compound of formula A of ‘810 according to the treatment regimens of Beaton because Beaton teaches the same compound for the same purpose of treating HAE.
Furthermore, Beaton teaches that formula A would be administered in a daily dose of 10 mg to 1000 mg (page 26, line 14), and that the compound may be administered in single or divided doses (page 27, line 19). Beaton teaches that the dosages are based on an average human subject having a weight of about 60kg to 70kg and that the physician will readily be able to determine doses for subjects whose weight falls outside this range (page 26, lines 20-22). Beaton also discloses pharmacokinetic studies in an animal model using a single oral dosage of 10 mg/kg (page 62, lines 6-10). It would have been prima facie obvious for one of ordinary skill in the art to begin optimization of the dosage of formula A with a 600mg dosage for a 60kg patient because Beaton suggests a dosage of 10 mg/kg. Furthermore, MPEP 2144.05(II)(A) states that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Thus it would have been prima facie obvious for one of ordinary still in the art to optimize the dosages of formula A within the range of 10-1000 mg, including the timing of divided daily dosages. One of ordinary skill in the art would have a reasonable expectation of success because teaches that formula A would be administered in a daily dose of 10 mg to 1000 mg in a single or divided dose and that the physician will readily be able to determine doses for subjects.
Regarding claim 80, Beaton teaches that plasma kallikrein plays a role in a number of inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients with a genetic deficiency in C1 esterase inhibitor suffer from HAE (page 1, lines 27-30). Administering plasma kallikrein inhibitors reduces the positive feedback amplification of the kallikrein system by the contact activation system through inhibiting activation of factor XII (page 3, lines 18-22). As the teachings of the prior art disclose the administration of the formula A of Beaton, which is the same drug as that of the instant claims, to the same patient population (HAE patients), and it would be obvious to do so at the same dosage of 600 mg, the results recited in instant claim 80 would necessarily flow, thereby meeting the instant claim limitations. One of ordinary skill in the art would have a reasonable expectation of success in blocking activation of the contact system for up to six hours because Beaton teaches that formula A is a plasma kallikrein inhibitor useful for the treatment of HAE and that plasma kallikrein inhibitors inhibit activation of factor XXII and thereby reduce amplification of the kallikrein system by the contact system.
Claims 66-100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 46-47, and 52-84 of copending Application No. 18/249,076 (reference application; claims filed 19 Apr 2023) in view of Beaton et al. (WO 2017/208005 Al; IDS 09/09/2022). Although the claims at issue are not identical, they are not patentably distinct from each other.
‘076 claim 46 recites a method for treating bradykinin mediated angioedema