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 .
Detailed Action
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 15 October 2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner. See attached copy of PTO-1449.
Status of Application
2. Applicant’s arguments/remarks filed 15 October 2025 are acknowledged. Claims 1-2, 5-6, 27-28, 33-34, and 37-41 are currently pending. Claims 3-4, 7-26, 29-32, 35-36, and 42-54 are cancelled. Claim 38 is amended. Claims 1-2, 5-6, 27-28, 33-34, and 37-41 are examined on the merits within.
Withdrawn Rejections
3. Applicant’s arguments, filed 15 October 2025, with respect to the 35 U.S.C. 112(b) Rejection have been fully considered and are persuasive. The 35 U.S.C. 112(b) Rejection of claim 38 has been withdrawn.
Maintained Rejections
Claim Rejections – 35 U.S.C. 103
4. 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.
5. Claim(s) 1-2, 6, 27-28, 33-34 and 37-41 is/are again rejected under 35 U.S.C. 103 as being unpatentable over Devries et al. (WO2020/036993) in view of Marambaud (WO2020/068719).
Devries et al. teach a pharmaceutical composition for treatment of a disease characterized by chronic inflammation associated with angiogenesis and fibrosis. The composition comprises a multi-kinase inhibitor such as pazopanib. See abstract. Disorders of chronic inflammation associated with angiogenesis and fibrosis include hereditary hemorrhagic telangiectasia. See page 1. For treatments wherein the multi-kinase inhibitor is pazopanib, about 0.0001-100 mg may be used, and treatment may occur for at least about 6 months. See page 74. The instant specification defines hemorrhagic locus as an anatomical location of a hemorrhage and/or lesion at which blood or other bodily fluid is escaping. See page 5. Devries et al. teach treatment of conditions having lesions. See page 74.
Devries et al. do not teach hemorrhagic locus, vascular density, or cardiac failure.
Marambaud teaches compositions for treating vascular lesions and hereditary hemorrhagic telangiectasia. See abstract. Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease or syndrome, is a hemorrhagic genetic disorder that leads to abnormal blood vessel formations (or vascular lesions), including prominently telangiectasis and arteriovenous malformations, in the skin, mucous membranes and organs, such as the liver, lung, gastrointestinal system, and brain of an afflicted subject. In its most severe manifestations, HHT can lead to highly debilitating and life-threatening events, such as severe epistaxis and internal bleeding. HHT is also associated with secondary complications, which include anemia, cerebral abscess and embolism following pulmonary AVMs, as well as high-output cardiac failure consecutive to liver AVMs. See paragraph [0004]. Active ingredients include pazopanib. See paragraph [0015]. Receptor tyrosine kinase (RTK) inhibitors treat a vascular lesion and/or bleeding and/or anemia in a subject. See paragraph [0006]. Figures 1A-1B show the effects of different treatments on number and diameter of arteriovenous malformations (AVMs), diameter of veins, and vascular density, including statistical comparisons. See paragraph [0008].
It would have been obvious to one of ordinary skill in the art as of the effective filing date of the invention to identify a hemorrhagic locus prior to administering pazopanib in an effective amount because Devries et al. teach treatment of hereditary hemorrhagic telangiectasia with pazopanib and Marambaud teaches that receptor tyrosine kinase inhibitors treat vascular lesions and/or bleeding in subjects with hereditary hemorrhagic telangiectasia. It would have been obvious to one of ordinary skill in the art as of the effective filing date of the invention to determine a first vascular density of a subject with hereditary hemorrhagic telangiectasia and administer pazopanib and then identify a second vascular density and modify the amount of pazopanib based on the results because Devries et al. teach treatment of hereditary hemorrhagic telangiectasia with pazopanib and Marambaud teaches the correlation between vascular density and hereditary hemorrhagic telangiectasia. It is well within the purview of the skilled artisan to modify dosing regimen by increasing or decreasing therapeutic amounts based on routine testing to determine the efficacy of the therapeutic agent. It would have been obvious to one of ordinary skill in the art as of the effective filing date of the invention to determine a cardiac failure in a subject prior to administering pazopanib in an effective amount because Devries et al. teach treatment of hereditary hemorrhagic telangiectasia with pazopanib and Marambaud teaches the correlation between hereditary hemorrhagic telangiectasia and cardiac failure including anemia, lung lesions and liver lesions.
6. Claim(s) 5 is/are again rejected under 35 U.S.C. 103 as being unpatentable over Devries et al. (WO2020/036993) in view of Marambaud (WO2020/068719) as applied to claims 1-2, 6, 27-28, 33-34 and 37-41 above and further in view of Beckman et al. (Orphanet Journal of Rare Diseases, 2020).
Devries et al. teach qualitative assessments of dermal fibroplasia and neovascularization at wound sites after two doses (minimal = 1, mild = 2, moderate = 3, marked = 4, and severe=5). See Example 9.
Devries et al. do not specifically teach determining a therapeutically effective amount as a function of the severity indicator.
Beckman et al. teach Hereditary Hemorrhagic Telangiectasia (HHT) is a rare inherited disorder characterized by development of mucocutaneous telangiectasis and visceral organ arteriovenous malformations, which can lead to recurrent, spontaneous bleeding and development of iron deficiency anemia. The primary objective of this study was to ascertain the relationship between epistaxis severity scores (ESS), laboratory values, genotype, and phenotype in HHT. Our secondary objective was to assess efficacy of systemic antifibrinolytic therapy in reducing ESS in HHT. See abstract. We demonstrate that the ESS predicts markers of iron deficiency anemia and that it can be used to both guide and monitor response to therapeutic interventions in patients with HHT. See Conclusion.
It would have been obvious to one of ordinary skill in the art as of the effective filing date of the invention to determine the effective amount of pazopanib to administer based on severity scores because Devries et al. teach it is known to measure the severity of neovascularization and Beckman et al. teach using the knowledge learned from severity scores to guide and monitor therapeutic interventions.
Response to Arguments
Applicant's arguments filed 15 October 2025 have been fully considered but they are not persuasive.
7. Applicants argued, “Devries lists a vast possibility of combinations of diseases and compounds but does not give the motivation to achieve the claimed invention. One would not be motivated to use pazopanib for treating HHT given the numerous list of possibilities for diseases and compounds. None of the Figures or Examples of Devries analyze the effect of pazopanib. One skilled in the art would not have been motivated to choose pazopanib as sole treatment as is used in the claim. The Office failed to address identifying a hemorrhagic locus and determining a therapeutically effective amount of pazopanib as a function of the hemorrhagic locus, determining vascular density, or cardiac failure in a subject.”
In response to applicant’s arguments, Devries specifically recites “In some embodiments, pazopanib is administered to a mammal, particularly a human being, to treat hereditary hemorrhagic telangiectasia.” See page 45. Thus the prior art envisions treating hereditary hemorrhagic telangiectasia with pazopanib. The prior art does not need to provide specific examples of the preferred embodiments but instead are analyzed as a whole. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). With regards to determining a therapeutically effective amount, Devries teaches that administering a multi-target inhibitor, multi-phase modulator, or multi-kinase inhibitor, such as axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, or pazopanib, is effective in mitigating or reducing a sign, symptom, or pathology, or reducing some other indicator of a disease or condition. See page 5. Thus there must be an indication of the disease and the active ingredient is then administered in an effective amount. Since the claims do not clarify how the effective amount is determined, the prior art of Devries meets this limitation. In addition, the claims do not preclude additional active ingredients. Marambaud teaches receptor tyrosine kinase (RTK) inhibitors treat a vascular lesion and/or bleeding and/or anemia in a subject. See paragraph [0006]. Figures 1A-1B show the effects of different treatments on number and diameter of arteriovenous malformations (AVMs), diameter of veins, and vascular density, including statistical comparisons. See paragraph [0008]. As defined in the instant specification, hemorrhagic locus is the anatomical location of a hemorrhage and/or lesion at which blood or other bodily fluid is escaping. See page 5. Since Marambaud teaches treating lesions, the lesion must be identified. Since the claims do not detail how the lesion is identified, the prior art meets this limitation. Thus, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the invention to identify a hemorrhagic locus prior to administering pazopanib in an effective amount because Devries et al. teach treatment of hereditary hemorrhagic telangiectasia with pazopanib and Marambaud teaches that receptor tyrosine kinase inhibitors treat vascular lesions and/or bleeding in subjects with hereditary hemorrhagic telangiectasia. It would have been obvious to one of ordinary skill in the art as of the effective filing date of the invention to determine a first vascular density of a subject with hereditary hemorrhagic telangiectasia and administer pazopanib and then identify a second vascular density and modify the amount of pazopanib based on the results because Devries et al. teach treatment of hereditary hemorrhagic telangiectasia with pazopanib and Marambaud teaches the correlation between vascular density and hereditary hemorrhagic telangiectasia. It would have been obvious to one of ordinary skill in the art as of the effective filing date of the invention to determine a cardiac failure in a subject prior to administering pazopanib in an effective amount because Devries et al. teach treatment of hereditary hemorrhagic telangiectasia with pazopanib and Marambaud teaches the correlation between hereditary hemorrhagic telangiectasia and cardiac failure including anemia, lung lesions and liver lesions.
Thus this rejection is maintained.
8. Applicants argued, “Beckman fails to teach using the severity score and determining the therapeutically effective amount of pazopanib as a function of severity indicator.”
In response to applicant’s arguments, Beckman teaches the ESS predicts markers of iron deficiency anemia and that it can be used to both guide and monitor response to therapeutic interventions in patients with HHT. See Conclusion. Devries teaches that administering a multi-target inhibitor, multi-phase modulator, or multi-kinase inhibitor, such as axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, or pazopanib, is effective in mitigating or reducing a sign, symptom, or pathology, or reducing some other indicator of a disease or condition. See page 5. Thus there must be an indication of the disease and the active ingredient is then administered in an effective amount. Since the claims do not clarify how the effective amount is determined, the prior art of Devries meets this limitation. Thus it would have been obvious to one of ordinary skill in the art as of the effective filing date of the invention to determine the effective amount of pazopanib to administer based on severity scores because Devries et al. teach it is known to measure the severity of neovascularization and Beckman et al. teach using the knowledge learned from severity scores to guide and monitor therapeutic interventions.
Thus this rejection is maintained.
Conclusion
9. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
10. No claims are allowed at this time.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA WORSHAM whose telephone number is (571)270-7434. The examiner can normally be reached Monday-Friday (8-5).
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/JESSICA WORSHAM/Primary Examiner, Art Unit 1615