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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission, filed on 22 December 2025, has been entered.
Status of Application, Amendments and/or Claims
The amendment and Applicant’s arguments, filed 22 December 2025, have been entered in full. Claims 1-62 are canceled. New claims 63-93 are added. Claims 63-93 are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 22 December 2025) was received and complies with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. It has been placed in the application file and the information referred to therein has been considered as to the merits.
Withdrawn Objections And/Or Rejections
The rejection to claims 1, 4-6, 9, 10, 12, 16-18, 28, 32-34, 37, 38, 40, 44-46, 49, 50, 51, 53, 55-62 under 35 U.S.C. 103 as being unpatentable over Kostic et al. (US 2016/0152718; published 6/2/16) in view of Timony et al. (US 2022/0281968; published 9/8/22, priority date 4/27/17) and Graham et al. (US 2019/0367622; published 12/5/19), as set forth at pages 3-9 of the previous Office Action (22 April 2025), is withdrawn in view of the amendment (22 December 2025).
The rejection to claims 1, 8, 12, 28, 32, 36, 40, 51, 53, 55-62 under 35 U.S.C. 103 as being unpatentable over Clinical Trials.gov Identifier NCT03633617 (first posted 8/16/2018) in view of Kostic et al. (US 2016/0152718; published 6/2/16) and Timony et al. (US 2022/0281 968; published 9/8/22, priority date 4/27/17), as set forth at pages 10-12 of the previous Office Action (22 April 2025), is withdrawn in view of the amendment (22 December 2025).
The rejection to claims 1, 11, 28, 32, 39, 51, 53, 55-62 under 35 U.S.C. 103 as being unpatentable over Kostic et al. (US 2016/0152718; published 6/2/16) in view of Timony et al. (US 2022/0281 968; published 9/8/22, priority date 4/27/17) and Matsuda et al. (US 2021/0139541; published 5/13/21, priority date 6/14/19), as set forth at page 12 of the previous Office Action (22 April 2025), is withdrawn in view of the amendment (22 December 2025).
The rejection to claims 1, 4-6, 10, 12, 28, 32-34, 38, 40, 49, 50, 51, 53, 54, 55 57-62 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 7-12, 14-16 of U.S. Patent No. 11,421,036 in view of Kostic et al. (US 2016/0152718; published 6/2/16) and Timony et al. (US 2022/0281 968; published 9/8/22, priority date 4/27/17), as set forth at page 12-18 of the previous Office Action (22 April 2025), is withdrawn in view of the amendment (22 December 2025).
The rejection to claims 1, 5, 6, 10, 12, 16-18, 28, 32-34, 38, 40, 44-46, 51, 53, 57-62 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7-11, 13-16, 19, 22-26, 28-30 of U.S. Patent No. 9,290,574 in view of in view of Kostic et al. (US 2016/0152718; published 6/2/16) and Timony et al. (US 2022/0281 968; published 9/8/22, priority date 4/27/17), as set forth at page 12-18 of the previous Office Action (22 April 2025), is withdrawn in view of the amendment (22 December 2025).
The rejection to claims 1, 4-6, 9-12, 16-18, 28, 33, 34, 37-40, 44-46, 55-62 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 10, 11, 14-20 of U.S. Patent No. 10,730,948 in view of Kostic et al. (US 2016/0152718; published 6/2/16) in view of Timony et al. (US 2022/0281968; published 9/8/22, priority date 4/27/17), as set forth at page 12-18 of the previous Office Action (22 April 2025), is withdrawn in view of the amendment (22 December 2025).
MATTER OF RECORD
All of the pending rejections are withdrawn. Therefore, the Examiner will not address Applicant’s arguments. Please see the New Rejections, below.
NEW CLAIM REJECTIONS/OBJECTIONS
Claim Rejections-35 USC § 112(a) or 35 U.S.C. 112 (pre-AIA ), First paragraph, Written description, New Matter.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 75, 76, 77, 85, 86 and 93 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a New Matter Rejection.
The specification as originally filed does not provide support for the invention as now claimed:
“..wherein the subject had two esophageal dilations prior to treatment..".
Applicant’s amendment, filed 22 December 2025, asserts that no new matter has been added, and states that support for the new claims can be found in the specification as originally found.
The Examiner cannot locate the teachings as recited in the instant rejected claims.
The Examiner has found the following teaching in the specification:
“In some embodiments, the subject has had one or more esophageal dilations” (see paragraph 0056). “A high percentage of subjects had a history of prior swallowed topical steroid use and prior esophageal dilations, as shown in Table 2” (see paragraph 0173).
The Examiner cannot find a teaching wherein the subject had two esophageal dilations prior to the treatment.
The specification as filed does not provide a written description or set forth the metes and bounds of this "limitations". By amending the claims to specifically recite, “wherein the subject had two esophageal dilations prior to the treatment”, the instant claims now recite limitations which were not disclosed in the specification as filed, and now change the scope of the instant disclosure as-filed.
Applicant is required to cancel the new matter in the response to this Office action. Alternatively, Applicant is invited to provide specific written support for the “limitations” indicated above or rely upon the limitations set forth in the specification as filed.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1. Claim 63-68, 87-90 are rejected under 35 U.S.C. 103 as being unpatentable over Kostic et al. (Reference of record; US 2016/0152718; published 6/2/16) in view of ClinicalTrials.gov NCT03633617 (Record History date of March 15, 2019, see page 3 and bottom of page 6) and Hudgens et al. (Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with budesonide oral suspension. Journal of Patient-Reported Outcomes 1:3, pages 1-11; 2017).
Kostic et al. teach a method for treating eosinophilic esophagitis (EoE) comprising administering an anti-IL-4 receptor (IL-4R) inhibitor (abstract and para 0004). Kostic et al. teach the anti-IL-4R inhibitor can be an anti-IL4R-alpha antibody or dupilumab (para 0009)(applies to claims 63 and 87). Kostic et al. teach an anti-IL-4R alpha antibody that is 100% identical to instant SEQ ID NO:1 and SEQ ID NO:2. (Sequence Search Result of record dated 28 March 2023(applies to claims 87 and 88). Kostic et al. teach subcutaneously administering the anti-IL-4R alpha antibody at a dose of about 300 mgs, once a week (paras 0033, 0062 and 0068) (applies to claims 63 and 87). Kostic et al. teach administering to subjects who are 12, 13, 14 or more than 15 years old (para 0029). Male and female subjects who are more than 15 years old would encompass a body weight greater than 40 kg (or greater than 88 pounds)(applies to claims 63 and 87). Kostic et al. teach subjects with a history of a diagnosis of EoE confirmed by documented, peak cell density of greater than or equal to 15 eos/hpf from esophageal histology biopsy specimens at both proximal and distal levels (para 00089) (applies to claims 66 and 89).
Kostic et al. teach do not teach using a Dysphagia Symptom Questionnaire (DSQ) or that the subjects have a DSQ score that is > 30 prior to treatment. Kostic et al. do not teach 24 weeks of treatment.
Clinical Trial NCT03633617 teaches a study to determine the efficacy and safety of administering dupilumab in adults and adolescent patients with Eosinophilic Esophagitis (EoE). The trial determines the efficacy of dupilumab treatment compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures (pages 9-10)(applies to claims 63 and 87). The trial teaches subcutaneously administering dupilumab (page 12). The trial teaches that patients are excluded, if the patients weighs 40 kg or less (page 16)(applies to claims 63 and 87). The trial teaches a documented diagnosis of EoE by endoscopic biopsy/baseline endoscopic biopsies. The trial teaches history (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening (page 16). The trial teaches a primary outcome measure includes changes in dysphagia symptom Questionnaire (DSQ) score. The trial teaches the DSQ is used to measure the frequency and intensity of dysphagia. The trial teaches DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia (pages 13-15).
Hudgens et al. teach that the DSQ was developed specifically to measure dysphagia associated with EoE (pages 1-2). Hudgens et al. teach that the aim of their analysis was to assess the psychometric properties of the DSQ, a symptom measure designed to specifically assess dysphagia frequency and severity in patients with EoE, using data from a phase 2 trial of budesonide oral suspension (BOS). Hudgens et al. teach that the ability to accurately quantify dysphagia symptoms in patients with EoE, using a validated patient-reported outcome measure, would aid the development of new pharmacologic agents, such as BOS, for the treatment of EoE. Hudgens et al. teach patients were aged from 11-40 years old. The patients participated in a 6-week screening period wherein the DSQ was completed daily. Hudgens et al. teach that patients with sufficient dysphagia and greater than 70% compliance with the DSQ, entered a 4-week single-blind placebo run and then eventually proceeded to treatment with BOS (page 2, right column).
Hudgens et al. teach that the DSQ (version 4.0) uses a daily recall period and comprises three Questions on the presence and severity of EoE dysphagia (Questions 1–3)(page 3, Table 1). Hudgens et al. teach all patients respond to Questions 1 and 2 and are required to have eaten solid foods. Question 1 is “Since you woke up this morning, did you eat solid food?”. The patients must answer “Yes” in order to proceed with the Questionnaire to Question 2. Question 2 is “Since you woke up this morning has food gone down slowly or been stuck in your throat?”. Hudgens et al. teach patients who respond ‘No’ to Question 2 are given a score of zero, and do not go on to answer Question 3 (the diary is recorded as completed for that day).
Hudgens et al. teach those patients that respond ‘Yes’ to Questions 1 and 2 move on to Question 3, which is scored on a five-point scale that infers severity of dysphagia based on the patient’s action to alleviate symptoms, ranging from “no action, it got better on its own” (a score of 0); “I had to drink liquid to get relief” (a score of 1); “I had to cough and/or gag to get relief” (a score of 2); “I had to vomit to get relief” (a score of 3) or “I had to seek medical attention” (a score of 4).
Hudgens et al. teach Question 1 is not included in the scoring algorithm on the severity of dysphagia, as the incidence of solid food avoidance is thought to be low in patients with EoE. Hudgens et al. teach that if a patient answered ‘No’ to Question 1, the remaining items on the DSQ are not scored (page 2). Hudgens et al. teach that the DSQ scoring algorithm (Table 1) was therefore constructed from the responses to Questions 2 and 3, to ensure that the final score was driven by the frequency and severity of dysphagia. To calculate the DSQ score, a minimum of eight diary entries are required for each 14-day period. Baseline DSQ scores are recorded during the 14-day period before randomization. Hudgens et al. teach that DSQ scores could theoretically range from 0 to 84, with a lower score indicating less frequent or less severe dysphagia (page 3, left column).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of treating a subject with EoE comprising administering 300 mg of dupilumab subcutaneously to the subject once a week, wherein the subject is 12 years or older and has a body weight over 40 kg, as taught by Kostic et al. by using a DSQ, as taught by Clinical Trial NCT03633617, wherein prior to the treatment, the subject has a DSQ score of 30 or higher, as taught by Hudgens et al.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
Kostic and Clinical Trial NCT03633617 teach subcutaneously administering dupilumab to EoE patients who are greater than 12 years of age and have a body weight greater than 40 kg. Clinical Trial NCT03633617 teaches primary outcomes of administering dupilumab to EoE patients after 24 weeks of treatment. Primary outcomes include measuring changes in the dysphagia symptom Questionnaire (DSQ) score after 24 weeks of treatment. The trial teaches the DSQ is used to measure the frequency and intensity of dysphagia. The trial teaches DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia.
Hudgens et al. teach patients participated in a 6-week screening period during wherein the DSQ was completed daily. Hudgens et al. teach that Question 1 of the DSQ is not given a score. Answering “Yes” to Question 1 only prompts the patient to Question 2. Answering ‘No’ to Question 2 gives a score of zero and the patient does not go on to answer Question 3. Answering “Yes” to Question 2 gives the patient a score of 2 and the patient proceeds to Question 3. Question 3 is based on the severity of dysphagia and on the patient’s action to alleviate symptoms, such as “no action, it got better on its own” (a score of 0).
A patient answering “Yes” to Question 2, every day, in the 14-day period (a score of 2) and answering Question 3 as “no action, it got better on its own” (a score of 0) every day in the 14-day period, would have a DSQ score of 28 (the scores from Question 2 + the scores from Question 3). This means the patient has had food that goes down slowly or gets stuck in the throat but no action was taken because it got better on its own. A patient with EoE wherein the patient’s action to alleviate symptoms in Question 3 was “no action, it got better on its own” (i.e. DSQ score under 30), may not need/desire treatment.
However, a DSQ score of 30 or more would mean that the patient is answering Question 3 wherein at least some day(s) they had to drink liquid to get relief (a score of 1); they had to cough and/or gag to get relief (a score of 2); they had to vomit to get relief (a score of 3) or they had to seek medical attention (a score of 4). This indicates more frequent or more severe dysphagia. It would be obvious that a patient with EoE would have a DSQ score > 30 prior to treatment.
Lastly, the functional language, recited in claims 63, 64, 65, 67, 68 and 90 are not active steps of the claimed method (e.g. achieves a decrease in DSQ score, relative to the subject’s DSQ score prior to the treatment of at least 10 point (of at least 20 points) after 24 weeks of treatment. The claims describe a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg and has a DSQ score of 30 or higher before administering dupilumab (applies to claims 63, 64, 65, 67, 68) or describe a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg (applies to claim 90).
.
1a. Claims 69-74, 91 and 92 are rejected under 35 U.S.C. 103 as being unpatentable over Kostic et al. in view of ClinicalTrials.gov NCT03633617 and Hudgens et al., as applied to claims 63 and 87 above, and further in view of Radin et al. (US 2019/0040126; published Feb 7, 2019, Reference submitted by Applicant, IDS 8/30/21).
The teachings of Kostic, ClinicalTrials.gov NCT03633617 and Hudgens are described above. The combined references do not teach that the subjects had prior esophageal dilations prior to treatment.
Radin et al. teach treating eosinophilic esophagitis (EoE) comprising administering an interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor such as an anti-IL-4R antibody (abstract). Radin et al. teach the anti-IL4R-alpha antibody can be dupilumab. Radin et al. teach subcutaneously administering dupilumab 300 mg once a week (paras 0024-0034,0093 and 0094). Radin et al. teach that to determine whether an EoE-related parameter has “improved,” the parameter is quantified at baseline and at one or more time-points after administration of the pharmaceutical composition of the present invention. Radin et al. teach that an EoE-related parameter may be measured at week 24 or longer, after the initial treatment with a pharmaceutical composition of the present invention (para 0066). Radin et al. teach that the methods herein are for the treatment of adults or adolescents. Radin et al. teach that an adult is ≥18 years of age and an adolescent is ≥12 and ≤18 years of age (para 0049). Male and female adults that are ≥18 years of age would encompass a body weight greater than 40 kg (or greater than 88 pounds). An adolescent male or female that is 16, 17 or 18 years of age would encompass a body weight greater than 40 kg (or greater than 88 pounds). Radin et al. teach that the patient has had a peak esophageal intraepithelial eosinophil count ≥15 eosinophils per high powered field (hpf) in the esophagus prior to or at the time of the treatment (para 0071)(applies to claim 79). Radin et al. teach that the patient has had at least one prior esophageal dilation (para 0007)(applies to claims 69-74, 91 and 92).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of treating a subject with EoE comprising administering 300 mg of dupilumab subcutaneously to the subject once a week, wherein the subject is 12 years or older and has a body weight over 40 kg wherein prior to the treatment, the subject has a DSQ score of 30 or higher, as taught by Kostic et al., Clinical Trial NCT03633617 and Hudgens et al., wherein the subject has had prior esophageal dilations prior to treatment, as taught by Radin.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
Radin et al. teach that esophageal dilation by endoscopy is currently used to treat esophageal stricture and increase esophageal distensibility, but that it is a surgical procedure that is invasive and may lead to complications such as perforation and bleeding. Based on the teachings, it would be obvious to include subjects who have had prior esophageal dilations prior to treatment in order to discern an effective therapy for this aspect of EoE.
2. Claims 78-84 are rejected under 35 U.S.C. 103 as being unpatentable over Radin et al. (US 2019/0040126; published Feb 7, 2019) in view of ClinicalTrials.gov NCT03633617 (Record History date of March 15, 2019, see page 3 and bottom of page 6).
Radin et al. teach treating eosinophilic esophagitis (EoE) comprising administering an interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor such as an anti-IL-4R antibody (abstract). Radin et al. teach the anti-IL4R-alpha antibody can be dupilumab. Radin et al. teach subcutaneously administering dupilumab 300 mg once a week (paras 0024-0034,0093 and 0094)(applies to claim 78). Radin et al. teach that to determine whether an EoE-related parameter has “improved,” the parameter is quantified at baseline and at one or more time-points after administration of the pharmaceutical composition of the present invention. For example, an EoE-related parameter may be measured at week 24 or longer, after the initial treatment with a pharmaceutical composition of the present invention (para 0066)(applies to claim 78). Radin et al. teach that the methods herein are for the treatment of adults or adolescents. Radin et al. teach that an adult is ≥18 years of age and an adolescent is ≥12 and ≤18 years of age (para 0049)(applies to claim 78). Male and female adults that are ≥18 years of age would encompass a body weight greater than 40 kg (or greater than 88 pounds). An adolescent male or female that is 16, 17 or 18 years of age would encompass a body weight greater than 40 kg (or greater than 88 pounds)(applies to claim 78). Radin et al. teach that the patient has had a peak esophageal intraepithelial eosinophil count ≥15 eosinophils per high powered field (hpf) in the esophagus prior to or at the time of the treatment (para 0071)(applies to claim 79). Radin et al. teach that the patient has had at least one prior esophageal dilation (para 0007)(applies to claims 81-84).
Radin et al. teach do not teach using a Dysphagia Symptom Questionnaire (DSQ).
Clinical Trial NCT03633617 teaches a study to determine the efficacy and safety of administering dupilumab in adults and adolescent patients with Eosinophilic Esophagitis (EoE). The trial determines the efficacy of dupilumab treatment compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures (pages 9-10)(applies to claim 87). The trial teaches subcutaneously administering dupilumab (page 12). The trial teaches that patients are excluded, if the patients weighs 40 kg or less (page 16)(applies to claim 87). The trial teaches a documented diagnosis of EoE by endoscopic biopsy/baseline endoscopic biopsies. The trial teaches history (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening (page 16). The trial teaches a primary outcome measure includes changes in dysphagia symptom Questionnaire (DSQ) score. The trial teaches the DSQ is used to measure the frequency and intensity of dysphagia. The trial teaches DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia (pages 13-15).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of treating a subject with EoE comprising administering 300 mg of dupilumab subcutaneously to the subject once a week, wherein the subject is 12 years or older and has a body weight over 40 kg, wherein the subject has a history of prior esophageal dilations as taught by Radin et al. by using a DSQ, as taught by Clinical Trial NCT03633617, wherein the subject achieves a decrease in DSQ, relative to the subjects’ DSQ score prior to the treatment of at least 20 points after 24 weeks of the treatment.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
Radin and Clinical Trial NCT03633617 teach subcutaneously administering dupilumab to EoE patients who are greater than 12 years of age and have a body weight greater than 40 kg. Radin and Clinical Trial NCT03633617 teach discerning the efficacy of treatment after 24 weeks. Clinical Trial NCT03633617 teaches a primary outcome of administering dupilumab to EoE patients is measuring changes in the dysphagia symptom Questionnaire (DSQ) score. The functional language recited in claims 78 and 80 are not active steps of the claimed method. The claims describe a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg (applies to claims 78 and 80).
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.
1. Claims 63-74, 78-84, 87-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6-12, 14-16 of U.S. Patent No. 11,421,036 in view of Radin et al. (US 2019/0040126; published Feb 7, 2019), ClinicalTrials.gov NCT03633617 (Record History date of March 15, 2019, see page 3 and bottom of page 6) and Hudgens et al. (Journal of Patient-Reported Outcomes 1:3, pages 1-11; 2017).
The instant claims are drawn to a method of treating a subject with eosinophilic esophagitis (EoE), comprising administering 300 mg of dupilumab subcutaneously to the subject once every week; wherein the subject is 12 years of age or older and has a body weight greater than 40 kg, wherein prior to the treatment, the subject had a Dysphagia Symptom Questionnaire (DSQ) score >_ 30, wherein the subject achieves a decrease in DSQ score, relative to the subject’s DSQ score prior to treatment of at least 10 points (at least 20 points) after 24 weeks of treatment. The claims are further drawn to wherein prior to the treatment, the subject had a peak esophageal intraepithelial eosinophil count of 15 or higher eosinophils per high power field ("eos/hpf"). The claim are further drawn to wherein the subject had one or more esophageal dilations prior to the treatment. The instant claims are further drawn to a method of treating a subject with EoE, comprising administering to the subject an anti-IL-4R antibody, wherein the anti-IL-4R antibody is a full antibody molecule of the IgG4 isotype, wherein the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) of SEQ ID NO: 1 and a light chain variable region (LCVR) of SEQ ID NO: 2; wherein the anti-IL-4R antibody is administered subcutaneously at a dose of 300 mg once every week; wherein the subject is 12 years of age or older and has a body weight greater than 40 kg;
The claims of U.S. Patent No. 11,421,036 teach a method of treating or ameliorating at least one symptom of eosinophilic esophagitis (EoE) in a subject, the method comprising administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) inhibitor, wherein the IL-4R inhibitor is an antibody or antigen-binding fragment thereof that binds IL-4Rα and comprises a heavy chain complementarity determining region (HCDR)1 comprising the amino acid sequence of SEQ ID NO:3, an HCDR2 comprising the amino acid sequence of SEQ ID NO:4, an HCDR3 comprising the amino acid sequence of SEQ ID NO:5, a light chain complementarity determining region (LCDR)1 comprising the amino acid sequence of SEQ ID NO:6, an LCDR2 comprising the amino acid sequence of SEQ ID NO:7, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:8, and wherein the IL-4R inhibitor is administered to the subject subcutaneously. The claims further teach wherein, prior to the onset of treatment the subject exhibits an esophageal eosinophilic infiltration of ≥15 eosinophils per high-power field as measured by esophageal biopsy. The claims of U.S. Patent No. 11,421,036 further teach wherein the subject is an adult. Adult male and adult female subjects would encompass a body weight greater than 40 kg (or greater than 88 pounds). The claims further teach wherein the IL-4R inhibitor is administered subcutaneously, wherein each dose of the IL-4R inhibitor is 300 mg and is administered once a week. The claims further teach wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. The claims further teach wherein the antibody or antigen-binding fragment thereof is dupilumab or a bioequivalent thereof.
The claims of U.S. Patent No. 11,421,036 do not teach using a Dysphagia Symptom Questionnaire (DSQ) or that the subjects have a DSQ score that is >_ 30 prior to treatment. The claims of U.S. Patent No. 11,421,036 do not teach wherein the subject had one or more esophageal dilation prior to treatment. The claims of U.S. Patent No. 11,421,036 do not teach 24 weeks of treatment.
Radin et al. teach treating eosinophilic esophagitis (EoE) comprising administering an interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor such as an anti-IL-4R antibody (abstract). Radin et al. teach the anti-IL4R-alpha antibody can be dupilumab. Radin et al. teach subcutaneously administering dupilumab 300 mg once a week (paras 0024-0034,0093 and 0094). Radin et al. teach that to determine whether an EoE-related parameter has “improved,” the parameter is quantified at baseline and at one or more time-points after administration of the pharmaceutical composition of the present invention. For example, an EoE-related parameter may be measured at week 24 or longer, after the initial treatment with a pharmaceutical composition of the present invention (para 0066). Radin et al. teach that the methods herein are for the treatment of adults or adolescents. Radin et al. teach that an adult is ≥18 years of age and an adolescent is ≥12 and ≤18 years of age (para 0049). Male and female adults that are ≥18 years of age would encompass a body weight greater than 40 kg (or greater than 88 pounds). An adolescent male or female that is 16, 17 or 18 years of age would encompass a body weight greater than 40 kg (or greater than 88 pounds). Radin et al. teach that the patient has had a peak esophageal intraepithelial eosinophil count ≥15 eosinophils per high powered field (hpf) in the esophagus prior to or at the time of the treatment (para 0071). Radin et al. teach that the patient has had at least one prior esophageal dilation (para 0007).
Clinical Trial NCT03633617 teaches a study to determine the efficacy and safety of administering dupilumab in adults and adolescent patients with Eosinophilic Esophagitis (EoE). The trial determines the efficacy of dupilumab treatment compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures (pages 9-10). The trial teaches subcutaneously administering dupilumab (page 12). The trial teaches that patients are excluded, if the patients weighs 40 kg or less (page 16). The trial teaches a documented diagnosis of EoE by endoscopic biopsy/baseline endoscopic biopsies. The trial teaches history (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening (page 16). The trial teaches a primary outcome measure includes changes in dysphagia symptom Questionnaire (DSQ) score. The trial teaches the DSQ is used to measure the frequency and intensity of dysphagia. The trial teaches DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia (pages 13-15).
Hudgens et al. teach that the DSQ was developed specifically to measure dysphagia associated with EoE (pages 1-2). Hudgens et al. teach that the aim of their analysis was to assess the psychometric properties of the DSQ, a symptom measure designed to specifically assess dysphagia frequency and severity in patients with EoE, using data from a phase 2 trial of budesonide oral suspension (BOS). Hudgens et al. teach that the ability to accurately quantify dysphagia symptoms in patients with EoE, using a validated patient-reported outcome measure, would aid the development of new pharmacologic agents, such as BOS, for the treatment of EoE. Hudgens et al. teach patients participated in a 6-week screening period wherein the DSQ was completed daily. Hudgens et al. teach that patients with sufficient dysphagia and greater than 70% compliance with the DSQ, entered a 4-week single-blind placebo run (page 2, right column). Hudgens et al. teach that the DSQ (version 4.0) uses a daily recall period and comprises three Questions on the presence and severity of EoE dysphagia (Questions 1–3)(page 3, Table 1). Hudgens et al. teach all patients respond to Questions 1 and 2 and are required to have eaten solid foods. Question 1 is “Since you woke up this morning, did you eat solid food?”. The patients must answer “Yes” in order to proceed with the Questionnaire to Question 2. Question 2 is “Since you woke up this morning has food gone down slowly or been stuck in your throat?”. Hudgens et al. teach patients who respond ‘No’ to Question 2 are given a score of zero, and do not go on to answer Question 3 (the diary is recorded as completed for that day). Hudgens et al. teach those patients that respond ‘Yes’ to Questions 1 and 2 move on to Question 3, which is scored on a five-point scale that infers severity of dysphagia based on the patient’s action to alleviate symptoms, ranging from “no action, it got better on its own” (a score of 0); “I had to drink liquid to get relief” (a score of 1); “I had to cough and/or gag to get relief” (a score of 2); “I had to vomit to get relief” (a score of 3) or “I had to seek medical attention” (a score of 4). Hudgens et al. teach Question 1 is not included in the scoring algorithm on the severity of dysphagia, as the incidence of solid food avoidance is thought to be low in patients with EoE. Hudgens et al. teach that if a patient answered ‘No’ to Question 1, the remaining items on the DSQ are not scored (page 2). Hudgens et al. teach that the DSQ scoring algorithm (Table 1) was therefore constructed from the responses to Questions 2 and 3, to ensure that the final score was driven by the frequency and severity of dysphagia. To calculate the DSQ score, a minimum of eight diary entries are required for each 14-day period. Baseline DSQ scores are recorded during the 14-day period before randomization. Hudgens et al. teach that DSQ scores could theoretically range from 0 to 84, with a lower score indicating less frequent or less severe dysphagia (page 3, left column).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of treating a subject with EoE comprising subcutaneously administering 300 mg of an IL-4R inhibitor once a week to an adult subject, wherein the IL-4R inhibitor is an antibody comprising a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2, as taught by the claims of U.S. Patent No. 11,421,036, wherein the subject had one or more esophageal dilation prior to treatment, as taught by Radin et al., and using a DSQ, as taught by Clinical Trial NCT03633617, wherein prior to the treatment, the subject has a DSQ score of 30 or higher, as taught by Hudgens et al.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
The administered antibody taught in the claims of U.S. Patent No. 11,421,0326 is 100% identical to the instant administered antibody (sequence search of record; Office Action March 28, 2023). In addition, both set of claims recite the same dosage, dosing frequency and route of administration. Both sets of claims encompass administering to adults who weigh over 40 kgs (over 88 lbs.).
The claims of U.S. Patent No. 11,421,0326 and Radin et al. reference teach administering dupilumab at the same dose, dosing frequency, route of administration to adults who weigh over 40 kgs (over 88 lbs.). Radin et al. teach that esophageal dilation by endoscopy is currently used to treat esophageal stricture and increase esophageal distensibility, but that it is a surgical procedure that is invasive and may lead to complications such as perforation and bleeding. Based on the teachings, it would be obvious to include subjects who have had prior esophageal dilations prior to treatment in order to discern an effective therapy for this aspect of EoE.
Clinical Trial NCT03633617 teach subcutaneously administering dupilumab to EoE patients who are adults and have a body weight greater than 40 kg. Radin and Clinical Trial NCT03633617 teach discerning the efficacy of treatment after 24 weeks, with Clinical Trial NCT03633617 teaching measuring changes in the dysphagia symptom Questionnaire (DSQ) score. Clinical Trial NCT03633617 and Hudgens et al teaches DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia.
Hudgens et al. teach patients participated in a 6-week screening period during wherein the DSQ was completed daily. Hudgens et al. teach that Question 1 of the DSQ is not given a score. Answering “Yes” to Question 1 only prompts the patient to Question 2. Answering ‘No’ to Question 2 gives a score of zero and the patient does not go on to answer Question 3. Answering “Yes” to Question 2 gives the patient a score of 2 and the patient proceeds to Question 3. Question 3 is based on the severity of dysphagia and on the patient’s action to alleviate symptoms, such as “no action, it got better on its own” (a score of 0).
A patient answering “Yes” to Question 2, every day, in the 14-day period (a score of 2) and answering Question 3 as “no action, it go better on its own” (a score of 0) every day in the 14-day period, would have a DSQ score of 28 (the scores from Question 2 + the scores from Question 3). This means the patient has had food that goes down slowly or gets stuck in the throat but no action was taken because it got better on its own. A patient with EoE wherein the patient’s action to alleviate symptoms in Question 3 was “no action, it got better on its own” (DSQ score under 30), may not need/desire treatment. However, a DSQ score of 30 or more would mean that the patient is answering Question 3 wherein at least some day(s) they had to drink liquid to get relief (a score of 1); they had to cough and/or gag to get relief (a score of 2); they had to vomit to get relief (a score of 3) or they had to seek medical attention (a score of 4). This indicates more frequent or more severe dysphagia. A patient with EoE having a DSQ score 30 or higher would desire/need treatment.
Lastly, the functional language, recited in claims are not active steps of the claimed method. The claims describe a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg and has a DSQ score of 30 or higher before administering dupilumab or describes a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg.
2. Claims 63-74, 78-84, 87-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 9-12, 15-20 of U.S. Patent No. 10,730,948 in view of Radin et al. (US 2019/0040126; published Feb 7, 2019), ClinicalTrials.gov NCT03633617 (Record History date of March 15, 2019, see page 3 and bottom of page 6) and Hudgens et al. (Journal of Patient-Reported Outcomes 1:3, pages 1-11; 2017).
The instant claims are recited above.
The claims of U.S. Patent No. 10,730,948 teach a method of treating or ameliorating at least one symptom or indication of eosinophilic esophagitis (EoE) comprising: (a) selecting a patient with a history of diagnosis of EoE wherein the patient has ≥15 eosinophils per high powered field (hpf) from a esophageal biopsy specimen; and (b) administering to the patient one or more doses of a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) inhibitor. The claims further teach wherein the symptom or indication of EoE is selected from the group consisting of eosinophilic infiltration of the esophagus, thickening of the esophageal wall, food refusal, vomiting, abdominal pain, heartburn, regurgitation, dysphagia and food impaction. The claims further teach wherein the pharmaceutical composition is administered subcutaneously to the patient and wherein each dose comprises 300 mg of the IL-4R inhibitor. The claims further teach wherein step (b) comprises: administering an initial dose of the pharmaceutical composition to the patient; followed by administering one or more subsequent doses of the pharmaceutical composition to the patient, wherein each subsequent dose is administered to the patient one week after the immediately preceding dose. The claims of U.S. Patent No. 10,730,948 further teach wherein the IL-4R inhibitor is an antibody or antigen-binding fragment thereof that binds IL-4Rα and prevents the interaction of IL-4 and/or IL-13 with a type 1 or type 2 IL-4 receptor, wherein the antibody or antigen-binding fragment thereof prevents the interaction of IL-4 with both type 1 and type 2 IL-4 receptors, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs—HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDRs—LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. The claims further teach wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1 and the LCVR comprises the amino acid sequence of SEQ ID NO: 2. The claims further teach wherein the IL-4R inhibitor is dupilumab or a bioequivalent thereof.
The claims of U.S. Patent No. 10,730,948 do not teach that the subject is 12 years of age or older and has a body weight of greater that 40 kgs. The claims of U.S. Patent No. 10,730,948 do not teach using a Dysphagia Symptom Questionnaire (DSQ) or that the subjects have a DSQ score that is >_ 30 prior to treatment. The claims of U.S. Patent No. 10,730,948 do not teach wherein the subject had one or more esophageal dilation prior to treatment. The claims of U.S. Patent No. 10,730,948 do not teach 24 weeks of treatment.
The teachings of Radin et al., ClinicalTrials.gov NCT03633617 and Hudgens et al. are described above.
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of treating or ameliorating at least one symptom or indication of eosinophilic esophagitis (EoE) comprising: (a) selecting a patient with a history of diagnosis of EoE wherein the patient has ≥15 eosinophils per high powered field (hpf) from a esophageal biopsy specimen; and (b) subcutaneously administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) inhibitor once a week, wherein the an interleukin-4 receptor (IL-4R) inhibitor is antibody comprising the heavy chain complementarity determining regions (HCDRs—HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDRs—LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2, as taught by the claims of U.S. Patent No. 10,730,948, wherein the subject had one or more esophageal dilation prior to treatment and is 12 years of age or older and weighs over 40 kgs, as taught by Radin et al., and using a DSQ, as taught by Clinical Trial NCT03633617, wherein prior to the treatment, the subject has a DSQ score of 30 or higher, as taught by Hudgens et al.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
The administered antibody taught in the claims of U.S. Patent No. 10,730,948 is 100% identical to the instant administered antibody (sequence search of record; Office Action October 28, 2024). In addition, both set of claims recite the same dosage, dosing frequency and route of administration.
The Radin et al. reference teach administering dupilumab at the same dose, dosing frequency, route of administration to EoE patients who are 12 years of age and older and who weigh over 40 kgs (over 88 lbs.). Radin et al. teach that esophageal dilation by endoscopy is currently used to treat esophageal stricture and increase esophageal distensibility, but that it is a surgical procedure that is invasive and may lead to complications such as perforation and bleeding. Based on the teachings, it would be obvious to include subjects who have had prior esophageal dilations prior to treatment in order to discern an effective therapy for this aspect of EoE.
Clinical Trial NCT03633617 teach subcutaneously administering dupilumab to EoE patients who are adults and have a body weight greater than 40 kg. Radin and Clinical Trial NCT03633617 teach discerning the efficacy of treatment after 24 weeks, with Clinical Trial NCT03633617 teaching measuring changes in the dysphagia symptom Questionnaire (DSQ) score. Clinical Trial NCT03633617 and Hudgens et al teaches DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia.
Hudgens et al. teach patients participated in a 6-week screening period during wherein the DSQ was completed daily. Hudgens et al. teach that Question 1 of the DSQ is not given a score. Answering “Yes” to Question 1 only prompts the patient to Question 2. Answering ‘No’ to Question 2 gives a score of zero and the patient does not go on to answer Question 3. Answering “Yes” to Question 2 gives the patient a score of 2 and the patient proceeds to Question 3. Question 3 is based on the severity of dysphagia and on the patient’s action to alleviate symptoms, such as “no action, it got better on its own” (a score of 0).
A patient answering “Yes” to Question 2, every day, in the 14-day period (a score of 2) and answering Question 3 as “no action, it go better on its own” (a score of 0) every day in the 14-day period, would have a DSQ score of 28 (the scores from Question 2 + the scores from Question 3). This means the patient has had food that goes down slowly or gets stuck in the throat but no action was taken because it got better on its own. A patient with EoE wherein the patient’s action to alleviate symptoms in Question 3 was “no action, it got better on its own” (DSQ score under 30), may not need/desire treatment. However, a DSQ score of 30 or more would mean that the patient is answering Question 3 wherein at least some day(s) they had to drink liquid to get relief (a score of 1); they had to cough and/or gag to get relief (a score of 2); they had to vomit to get relief (a score of 3) or they had to seek medical attention (a score of 4). This indicates more frequent or more severe dysphagia. A patient with EoE having a DSQ score 30 or higher would desire/need treatment.
Lastly, the functional language, recited in claims are not active steps of the claimed method. The claims describe a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg and has a DSQ score of 30 or higher before administering dupilumab or describes a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg.
3. Claims 63-74, 78-84, 87-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7-11, 13, 31-33, 38-43 of U.S. Patent No. 9,290,574 in view of Radin et al. (US 2019/0040126; published Feb 7, 2019), ClinicalTrials.gov NCT03633617 (Record History date of March 15, 2019, see page 3 and bottom of page 6) and Hudgens et al. (Journal of Patient-Reported Outcomes 1:3, pages 1-11; 2017).
The instant claims are recited above.
The claims of U.S. Patent No. 9,290,574 teach a method of treating or ameliorating at least one symptom or indication of eosinophilic esophagitis (EoE) comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) inhibitor to a subject in need thereof. The claims further teach wherein the symptom or indication of EoE is selected from the group consisting of eosinophilic infiltration of the esophagus, thickening of the esophageal wall, food refusal, vomiting, abdominal pain, heartburn, regurgitation, dysphagia and food impaction. The claims further teach wherein the IL-4R inhibitor is an antibody or antigen-binding fragment thereof that binds IL-4Rα and prevents the interaction of IL-4 and/or IL-13 with a type 1 or type 2 IL-4 receptor, wherein the antibody or antigen-binding fragment thereof prevents the interaction of IL-4 and IL-13 with both type 1 and type 2 IL-4 receptors. The claims of U.S. Patent No. 9,290,574 further teach wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8 and wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1 and the LCVR comprises the amino acid sequence of SEQ ID NO: 2. The claims further teach wherein the IL-4R inhibitor is dupilumab or a bioequivalent thereof. The claims of U.S. Patent No. 9,290,574 further teach a method of treating or ameliorating at least one symptom or indication of eosinophilic esophagitis (EoE) comprising: (a) selecting a subject who exhibits at least one symptom or indication of EoE, wherein the subject has an elevated level of a biomarker selected from the group consisting of esophagus eosinophils, eotaxin-3, periostin, serum IgE (total and allergen-specific), IL-13, IL-5, TARC, TSLP, serum ECP, and EDN; and (b) administering a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) inhibitor to the subject in need thereof and wherein the subject is selected on the basis of exhibiting ≧15 eosinophils per high powered field (hpf) in the esophagus prior to or at the time of the treatment (“baseline”). The claims further teach wherein the indication is selected from the group consisting of eosinophilic infiltration of the esophagus, thickening of the esophageal wall, food refusal, vomiting, abdominal pain, heartburn, regurgitation, dysphagia and food impaction.
The claims of U.S. Patent No. 9,290,574 do not teach dose, dosing schedule or route of administering the IL-4R inhibitor. The claims of U.S. Patent No. 9,290,574 do not teach that the subject is 12 years of age or older and has a body weight of greater that 40 kgs. The claims of U.S. Patent No. 9,290,574 do not teach using a Dysphagia Symptom Questionnaire (DSQ) or that the subjects have a DSQ score that is >_ 30 prior to treatment. The claims of U.S. Patent No. 9,290,574 do not teach wherein the subject had one or more esophageal dilation prior to treatment. The claims of U.S. Patent No. 9,290,574 do not teach 24 weeks of treatment.
The teachings of Radin et al., ClinicalTrials.gov NCT03633617 and Hudgens et al. are described above.
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of treating or ameliorating at least one symptom or indication of eosinophilic esophagitis (EoE) comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) inhibitor to a subject in need thereof, wherein the symptom or indication of EoE is selected from the group consisting of eosinophilic infiltration of the esophagus, thickening of the esophageal wall, food refusal, vomiting, abdominal pain, heartburn, regurgitation, dysphagia and food impaction, wherein the interleukin-4 receptor (IL-4R) inhibitor is an antibody that comprises the heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2 or wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8 and wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1 and the LCVR comprises the amino acid sequence of SEQ ID NO: 2, as taught by the claims of U.S. Patent No. 9,290,574, wherein the antibody is administered subcutaneously once a week at a dose of 300 mg to a subject that had one or more esophageal dilation prior to treatment, is 12 years of age or older and weighs over 40 kgs, as taught by Radin et al., and using a DSQ, as taught by Clinical Trial NCT03633617, wherein prior to the treatment, the subject has a DSQ score of 30 or higher, as taught by Hudgens et al.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
The administered antibody taught in the claims of U.S. Patent No. 9,290,574 is 100% identical to the instant administered antibody (sequence search of record; Office Action March 28, 2023).
Radin et al. teach subcutaneously administering dupilumab 300 mg once a week to EoE patients who are 12 years of age and older and who weigh over 40 kgs. Radin et al. teach that esophageal dilation by endoscopy is currently used to treat esophageal stricture and increase esophageal distensibility, but that it is a surgical procedure that is invasive and may lead to complications such as perforation and bleeding. Based on the teachings, it would be obvious to include subjects who have had prior esophageal dilations prior to treatment in order to discern an effective therapy for this aspect of EoE.
Clinical Trial NCT03633617 teach subcutaneously administering dupilumab to EoE patients who are adults and have a body weight greater than 40 kg. Radin and Clinical Trial NCT03633617 teach discerning the efficacy of treatment after 24 weeks, with Clinical Trial NCT03633617 teaching measuring changes in the dysphagia symptom Questionnaire (DSQ) score. Clinical Trial NCT03633617 and Hudgens et al teaches DSQ scores can range from 0 to 84, with a lower score indicating less-frequent or less-severe dysphagia.
Hudgens et al. teach patients participated in a 6-week screening period during wherein the DSQ was completed daily. Hudgens et al. teach that Question 1 of the DSQ is not given a score. Answering “Yes” to Question 1 only prompts the patient to Question 2. Answering ‘No’ to Question 2 gives a score of zero and the patient does not go on to answer Question 3. Answering “Yes” to Question 2 gives the patient a score of 2 and the patient proceeds to Question 3. Question 3 is based on the severity of dysphagia and on the patient’s action to alleviate symptoms, such as “no action, it got better on its own” (a score of 0).
A patient answering “Yes” to Question 2, every day, in the 14-day period (a score of 2) and answering Question 3 as “no action, it go better on its own” (a score of 0) every day in the 14-day period, would have a DSQ score of 28 (the scores from Question 2 + the scores from Question 3). This means the patient has had food that goes down slowly or gets stuck in the throat but no action was taken because it got better on its own. A patient with EoE wherein the patient’s action to alleviate symptoms in Question 3 was “no action, it got better on its own” (DSQ score under 30), may not need/desire treatment. However, a DSQ score of 30 or more would mean that the patient is answering Question 3 wherein at least some day(s) they had to drink liquid to get relief (a score of 1); they had to cough and/or gag to get relief (a score of 2); they had to vomit to get relief (a score of 3) or they had to seek medical attention (a score of 4). This indicates more frequent or more severe dysphagia. A patient with EoE having a DSQ score 30 or higher would desire/need treatment.
Lastly, the functional language, recited in claims are not active steps of the claimed method. The claims describe a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg and has a DSQ score of 30 or higher before administering dupilumab or describes a property of dupilumab after 24 weeks of treatment when 300 mg is subcutaneously administered once a week to a subject with EoE, wherein the subject is 12 years or older and has a body weight over 40 kg.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REGINA M DEBERRY whose telephone number is (571)272-0882. The examiner can normally be reached M-F 9:00-6:30 pm (alt Fri).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional Questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/R.M.D/Examiner, Art Unit 1647 3/3/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647