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 4 May 2026 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. Receipt of the Request for Continued Examination (RCE) under 37 C.F.R. 1.114 and Applicants’ Arguments/Remarks, all filed 4 May 2026 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. Claims 1-2, 5-6, 27-28, 33-34, and 37-41 are examined on the merits within. No amendments have been made.
Continued Examination Under 37 C.F.R. 1.114
3. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4 May 2026 has been entered.
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 4 May 2026 have been fully considered but they are not persuasive.
7. Applicants argued, “Devries lists a vast possibility of combinations of diseases and compounds but provides no reason to select pazopanib. One would not be motivated to use pazopanib for treating HHT given the numerous list of possibilities for diseases and compounds. One would not have predicted that pazopanib would have been effective at treating HHT. The Declaration explains that the data in Devries demonstrates unpredictable nature of identifying a therapeutic for treatment of diseases such as HHT. Figure 5 shows that not all kinase inhibitors are equal but instead have a specific spectrum of kinase inhibition. Example 3 and Example 5 show further evidence of unpredictable behavior. Off target effects can exacerbate disease symptoms showing unpredictability in the art. A skilled artisan would not have been guided to treat HHT using pazopanib. Marambaud and Beckman fail to cure the deficiencies. There is a lack of guidance for patient specific dosing or treatment duration of HHT. The prior art does not teach determining a patients vascular density. The prior art does not teach determining a cardiac failure in a patient.”
The Declaration under 37 CFR 1.132 filed 4 May 2026 is insufficient to overcome the rejection of claims 1-2, 5-6, 27-28, 33-34, and 37-41 based upon 35 U.S.C. 103 as set forth in the last Office action because:
It is first noted that claim 1 is directed to a method of treating a subject with a hereditary hemorrhagic telangiectasia, not a method of treating hereditary hemorrhagic telangiectasia. Thus the patient must have the condition, however the body of the claim does not state that the condition is treated with pazopanib. Instead, a hemorrhagic locus is identified in a patient with HHT and a therapeutically effective amount of pazopanib is determined as a function of the hemorrhagic locus, and then administering the amount of pazopanib to the subject for 6 months. There is no mention that HHT is effectively treated or diminished.
However, 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)).
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. Devries specifically recites about 15-20 mg of pazopanib may be administered per lesion. See page 74. Thus pazopanib is administered for patients with HHT and to patients with lesions. Devries also recites “For treatment of conditions having lesions, the multi-kinase inhibitor is administered by injection into the lesion. The amount of the multi-kinase inhibitor administered will depend upon the size of the lesion being treated.” See page 68. Thus a lesion must be identified and then an effective amount determined. Even if Devries does not provide data specifically regarding pazopanib, the prior art does teach treating a lesion with pazopanib and determining an effective amount based on the lesion identified. Devries also teaches that treatment occurs as long as needed, including values of at least about 6 months. See page 74. These statements regarding drugs, ailments, and duration are not long lists to pick and choose from, but instead specific embodiments showing amounts and duration of effectively administering each drug for specific diseases and conditions thereof. Since the claims do not clarify how the effective amount is determined, the prior art of Devries meets this limitation. Even if the data of the multi-kinase inhibitors shows varying effects for various drugs, the prior art still teaches administration of pazopanib to patients with HHT and patients with lesions that have been identified, which reads on the instant claims. This does not equate to unpredictable. It is noted that the claims do not preclude additional active ingredients. The prior art of Marambaud was provided as further support correlating lesions with HHT. 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). 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]. 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. Changing doses based on measurements showing effectiveness should be routine in disease treatment. 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. 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.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
8. All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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
9. No claims are allowed at this time.
10. 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).
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, Robert Wax can be reached at 571-272-0623. 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.
/JESSICA WORSHAM/Primary Examiner, Art Unit 1615
Prosecution Insights