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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/332,628 and 63/389,444, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. A claim by claim analysis indicated a lack of support for CLAD in applications No. 63/389,444 and 63/332,628; thus claims 1-3 received a priority date of 04/18/2023. A claim by claim analysis indicated a lack of support for mild or moderate BOS in application No. 63/332,628; thus claims 12-15, 16-20, 41-42, 45-46, 50, , 55-58 received a priority date of 07/15/2022. Claim 11 received a priority date of 4/19/2022.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 11-20, 41-42, 45-46, 50, 55-58 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The parentheses around belumosudil in claims 1-3, 11-20, 41-42, 45-46, 50, 55-58 renders the claims 1-3, 11-20, 41-42, 45-46, 50, 55-58 indefinite because it is unclear whether the limitations within the parentheses are a required part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by PEEL (PEEL et al., WO 2022150676 A1, published 2022-07-14, effective filing date 1/11/2021).
PNG
media_image1.png
291
860
media_image1.png
Greyscale
PNG
media_image2.png
265
909
media_image2.png
Greyscale
The reference Peel teaches (reference claims):
This anticipates claims 1-3.
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.
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.
Claim(s) 1-3, 11-20, 41-42, 45-46, 50, 55-58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jagasia (Jagasia et al., ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease, J Clin Oncol 39, 1888-1898(2021)) in view of Pham (Pham et al., Updated prevalence, predictors and treatment outcomes for bronchiolitis obliterans syndrome after allogeneic stem cell transplantation, Respiratory Medicine 177 (2021) 106286) further in view of Vos(Vos et al., Pirfenidone in restrictive allograft syndrome after lung transplantation: A case series, Am J Transplant. 2018;18:3045–3059).
The reference Jagasia teaches “A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs)”(abstract) and “This phase IIa, dose-finding, open-label study was con ducted at seven centers in the United States. Eligible patients were allogeneic bone marrow transplant or alloHCT recipients of age ≥ 18 years with persistent cGVHD manifestations after having received one to three prior systemic LOTs and who were receiving CS treatment with or without a calcineurin inhibitor and/or concurrent extra corporeal photopheresis. Belumosudil was continued until cGVHD progression or unacceptable toxicity”(page 1889, [allogeneic hematopoietic cell transplant (alloHCT), page 1888]).
This helps to teach claims 41-42 and 58.
The reference Jagasia teaches (page 16):
PNG
media_image3.png
350
361
media_image3.png
Greyscale
This helps to teach claim 45.
The reference Jagasia teaches seven cycles (figure 4, page 1896). This helps to teach claim 50, 55-56.
The reference Jagasia teaches “Fibrotic cGVHD manifestations, including fasciitis, ocular fibrosis, cutaneous sclerosis, and bronchiolitis obliterans syndrome, are notoriously difficult to treat. eat.18,31-33 As a ROCK2 inhibitor, belumosudil has been shown to decrease inflammation, restore immune homeostasis, and decrease fibrosis.23,24,34 In our study, responses were achieved in patients with fibrotic manifestations in the lungs, joints and/or fascia, and eyes. These responses were observed in some cases after ˃ 24 weeks of treatment,34 further highlighting the need to sustain effective therapy to achieve clinical benefit, particularly in patients with difficult-to-treat disease. In summary, belumosudil is a selective ROCK2 inhibitor with a novel mechanism of action that targets both inflammation and fibrosis in cGVHD.23 Belumosudil was well tolerated and achieved clinically meaningful responses in patients with cGVHD across all dose regimens evaluated”(page 1896) and “Belumosudil demonstrated a significant reduction of lung and skin fibrosis in animal models of bronchiolitis obliterans syndrome and sclerodermatous cGVHD, respectively,24 which was consistent with the central role of ROCK in facilitating multiple fibrotic pathways.25”(page 1889).
This helps to teach claims 1-3 and 11-15.
The reference Jagasia teaches “Belumosudil was administered orally in 28-day cycles until disease progression or unacceptable toxicity”(page 1889).
This helps to teach claim 16.
The reference Jagasia teaches “Patients were enrolled into three sequential cohorts: cohort one received belumosudil 200 mg once daily, cohort two received belumosudil 200 mg twice daily (twice a day), and cohort three received belumosudil 400 mg once daily”(page 1889).
This helps to teach claim 17-20.
The reference Jagasia teaches(page 1890):
PNG
media_image4.png
75
462
media_image4.png
Greyscale
PNG
media_image5.png
93
475
media_image5.png
Greyscale
PNG
media_image6.png
78
440
media_image6.png
Greyscale
This helps to teach claim 57.
The reference Jagasia teaches “Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD” and “The baseline median CS dose (mg/kg/d prednisone equivalent) was 0.22, 0.19, and 0.17 across cohorts, respectively. Patients in cohort 1 had received a median of three prior LOTs whereas patients in cohorts 2 and 3 had received a median of two prior LOTs. Seventy-three percent (35 of 48, data not available for six patients) of patients were refractory to their last LOT before study enrollment”(page 1891).
This helps to teach claim 46.
The reference Jagasia does not teach CLAD or RAS (claims 1-3) or mild or moderate BOS (claims 11-20, 41-42, 45, 50, 55-58) or lung transplantation (claims 11-12)or the specific SR-cGVHD(claim 46).
The reference Pham teaches “Bronchiolitis obliterans syndrome (BOS) is a severe and often fatal complication of allogeneic haematopoietic stem cell transplantation (HSCT), characterised by airflow obstruction. BOS is thought to arise from allo-recognition of lung antigens leading to intraluminal/peri bronchiolar inflammation, fibrosis and eventual irreversible narrowing of terminal airways [1,2]”(page 1) and “BOS is a common and serious complication following HSCT, increasingly recognised following establishment of recent consensus diagnostic criteria. Our study suggests that BOS often leads to severe and progressive airflow obstruction. Early immunosuppression, compared to late immunosuppression, may slow lung function deterioration. Further research is urgently needed to identify efficacious preventative and treatment strategies to reduce morbidity and mortality from BOS”(page 4).
The reference Vos teaches “Restrictive allograft syndrome (RAS) was recently identified as a rare and distinct novel phenotype of chronic lung allograft dysfunction (CLAD) following lung transplantation (LTx), besides bronchiolitis obliterans syndrome (BOS).1‒4 RAS is characterized by restrictive pulmonary physiology and persistent pleuroparenchymal abnormalities, such as peripheral ground‐glass opacities, consolidation, traction bronchiectasis, architectural distortion, and (sub)pleural thickening on chest computed tomography (CT) scan.1‒3,5‒8 On histology, obliterative bronchiolitis (OB), together with pleuroparenchymal fibroelastosis, nonspecific interstitial pneumonia, or other interstitial and fibrotic changes can be seen,9‒11 which is associated with marked local T and B cell accumulation.12,13 Importantly, RAS carries an unfavorable prognosis with a median survival of 1‐1.5 years after disease onset.1,2,14 Adequate treatment options are currently lacking, except perhaps retransplantation in well‐selected cases.15 RAS may, however, redevelop in some patients after redo‐transplantation.15 Therefore, pharmacological therapy for RAS is an unmet medical need and novel treatment options for RAS are urgently needed. Pirfenidone, which has anti‐inflammatory and antifibrotic properties and is approved for treatment of idiopathic pulmonary fibrosis (IPF), may be such a drug.16 We previously reported on a first RAS patient treated with pirfenidone, demonstrating relative stabilization of spirometry and of specific CT features after 3 months (subpleural consolidations and ground‐glass opacities).17 Interestingly, stabilization of pulmonary function with pirfenidone was later also shown in a case of BOS.18”(page 3046) and “However, perhaps earlier initiation of treatment after RAS onset (ie, in case of “early stage disease”) may even prove to be more efficacious, which needs to be further studied”(page 3056). The reference also teaches “The dismal prognosis of RAS and the lack of efficacious medical therapeutic options (except perhaps lung redo‐transplantation in selected cases) provide a strong rationale for a novel treatment approach of this devastating condition. As such, the pathophysiologic mechanisms leading to tissue fibrosis in the lung allograft in RAS are thought to be, at last partially, similar to those in IPF.2,3,9‒11 Therefore, antifibrotic therapies may contribute to maintenance of allograft function and improved outcomes in RAS”(page 3052) and “Since pulmonary GvHD is characterized by small airways disease, obliteration, and sometimes concurrent (pleuro‐) parenchymal fibrosis/fibro‐elastosis (similar to RAS after LTx), pa tients with pulmonary GvHD may theoretically possibly also benefit from pirfenidone treatment, as was recently demonstrated with another antifibrotic drug—nintedanib—in 2 patients with fibrotic lung disease after allogeneic hematopoietic stem cell transplantation.33”(page 3054).
This helps to teach claims 1-3, and 11-20, 41-42, 45-46, 50, 55-58.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Jagasia with Vos because both suggest anti‐inflammatory and antifibrotic drugs to treat transplant recipients who suffer from transplant rejection. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Jagasia with Vos and Pham because Vos and Pham suggest early treatment of lung transplant rejection to slow lung function deterioration. One would be motivated to do so to treat the disease as early as possible (i.e. when the disease is only mild or moderate) to slow lung function deterioration. Jagasia suggests Belumosudil to treat bronchiolitis obliterans syndrome. Vos and Pham suggest treating lung transplant rejections early to protect lung function. Thus one would have a reasonable expectation of success because Belumosudil is already suggested to treat bronchiolitis obliterans syndrome and treating BOS at earlier stages is recommended.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Jagasia with Vos because both suggest an anti‐inflammatory and antifibrotic drug to treat transplant recipients who suffer from transplant rejection that relate to lung fibrotic changes. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have substituted one (pirfenidone) anti‐inflammatory and antifibrotic drugs with another anti‐inflammatory and antifibrotic drug (Belumosudil) for the same purpose of treating fibrotic lung damage related to transplant rejection (including BOS, CLAD or RAS). This substitution is likely to have a reasonable expectation of success because it is also support by the suggestion that one antifibrotic drug could replace another for a different pulmonary fibrosis disease page 3054 of VOS (nintedanib with pirfenidone). One would be motivated to do so to explore possible improvements in treat options for fibrotic lung damage caused by lung transplant rejection.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Jagasia with Vos because both suggest an anti‐inflammatory and antifibrotic drug to treat transplant recipients who suffer from transplant rejection that relate to lung fibrotic changes. It would have been obvious to treat SR-cGVHD because it is implicit to one of ordinary skill in the art to treat diseases that are resistant to steroid treatment with a different non- steroid treatment as demonstrated by the treatment of refractory patient population in the reference Jagasia. The specific amounts and time frames to classify as SR cGVHD are not taught, however, one would be motivated to treat SR-cGVHD populations with a different treatment besides a steroid that the disease may not be resistant against. One would have a reasonable expectation of success because one is treating them with an alternate non- steroid treatment.
Conclusion
Claims 1-3, 11-20, 41-42, 45-46, 50, 55-58 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALISON AZAR HASTINGS whose telephone number is (703)756-4584. The examiner can normally be reached Mon-Thurs 7:30am-5pm EST Friday 7:30-4pm EST (every other Friday off).
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, Kortney Klinkel can be reached at (571) 270-5239. 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.
/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627
Prosecution Insights