VANDA PHARMACEUTICALS INC.

Patent Trials and Appeals Board

Mar 14, 2022

2021002304 (P.T.A.B. Mar. 14, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 14/917,098 03/07/2016 Mihael H. POLYMEROPOULOS VAND-0121-US 6318 23550 7590 03/14/2022 HOFFMAN WARNICK LLC 540 Broadway 4th Floor Albany, NY 12207 EXAMINER CRAIGO, BAHAR ALAWI ART UNIT PAPER NUMBER 1623 NOTIFICATION DATE DELIVERY MODE 03/14/2022 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): PTOCommunications@hoffmanwarnick.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte MIHAEL H. POLYMEROPOULOS, LOUIS WILLIAM LICAMELE, and CHRISTIAN LAVEDAN __________ Appeal 2021-002304 Application 14/917,098 Technology Center 1600 __________ Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and RACHEL H. TOWNSEND, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a method for treating an individual having a CYR61-mediated condition. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the Real Party in Interest as Vanda Pharmaceuticals Inc. (see Appeal Br. 1). We have considered the Specification filed Mar. 7, 2016 (“Spec.”); Final Rejection of Feb. 13, 2020 (“Final Act.”); Appeal Brief filed Sept. 13, 2020 (“Appeal Br.”); Examiner’s Answer filed Dec. 15, 2020 (“Ans.”); and Reply Brief filed Feb. 12, 2021 (“Reply Br.”). Appeal 2021-002304 Application 14/917,098 2 Statement of the Case Background “The gene cystine[sic]-rich, angiogenic inducer, 61 (CYR61) is one member of the CCN gene family, which encode cysteine-rich secreted proteins involved with differentiation and cell growth. CYR61 is known, among other things, to mediate cell adhesion and enhance angiogenesis” (Spec. 1). “Individuals with proliferative diabetic retinopathy (PDR) have been shown to have increased levels of TGB-β [sic, TGF-β], which induces CYR61 expression” (id.). The Specification teaches the inventors “unexpectedly discovered that members of two known classes of compounds - anthracyclines and statins - are capable of downregulating expression of the CYR61 gene, making them useful in treating CYR61-mediated conditions” (Spec. 2). The Claims Claims 1, 5, 17-21, 23, and 24 are on appeal. Claims 1 and 20 are independent claims, are representative, and read as follows: 1. A method of treating a patient diagnosed with proliferative diabetic retinopathy (PDR) and having increased expression of the CYR61 gene as compared to the expression expected in an individual without PDR, the method comprising: orally administering to the patient an amount of at least one anthracycline effective to decrease expression of the CYR61 gene in the patient by at least about 2-fold. 20. In a method of treating an individual having a CYR61- mediated condition, the improvement comprising: selecting for treatment an individual exhibiting increased expression of the CYR61 gene, as compared to an individual not having the CYR-mediated condition; and administering to the individual having the CYR61- Appeal 2021-002304 Application 14/917,098 3 mediated condition an amount of at least one anthracycline effective to decrease expression of the CYR61 gene by at least about 2-fold, wherein the CYR61-mediated condition is selected from a group consisting of: neovascular glaucoma, macular degeneration, inflammatory neovascularization, Crohn’s disease, ulcerative colitis, retinal neovascularization, retinal vascular disorders, tumor vascularization, cancer angiogenesis, metastasis, rheumatoid arthritis, and fibrosis. The Rejections A. The Examiner rejected claims 20, 21, and 24 under 35 U.S.C. § 103 as obvious over Schulze2 and You3 (Final Act. 4-6). B. The Examiner rejected claims 1, 5, 17-19, and 23 under 35 U.S.C. § 103 as obvious over Schulze, You, and Guadana4 (Final Act. 8-9). Because both of these rejections share the same issues and overlapping prior art, and because Appellant does not separately argue these two rejections, we will consider these rejections together. The Examiner finds Schulze teaches a method of treating an ocular neovascularization using “an antineoplastic agent like an anthracycline, preferably doxorubicin . . . in a therapeutically effective dose” (Final Act. 4). The Examiner acknowledges that Schulze does not teach “increased 2 Schulze et al., US 2010/0034749 A1, published Feb. 11, 2010. 3 You et al., Cysteine-rich 61, a Member of the CCN Family, as a Factor Involved in the Pathogenesis of Proliferative Diabetic Retinopathy, 50(7) Investigative Opthamology & Visual Sci. 3447-55 (2009). 4 Guadana et al., Ocular Drug Delivery, 12(3) The AAPS J. 348-60 (2010). Appeal 2021-002304 Application 14/917,098 4 expression of the CYR61 gene as compared to the expression expected in a non-diseased individual” (id.). The Examiner finds You teaches “CYR61 mRNA and protein were significantly expressed in the retina of streptozocin-induced diabetic rat”; that “CYR61 is involved in ocular angiogenesis”; and that an “anti-CYR61 antibody significantly inhibited retinal neovascularization in the mouse oxygen-induced retinopathy (OIR) model” (Final Act. 5). The Examiner finds You concludes that “CYR61 is involved in the pathogenesis of proliferative diabetic retinopathy and may be a useful target for treatment” (id.). The Examiner finds it obvious to treat “an individual having a retinal vascular disorder including retinal vascularization, and exhibiting increased expression of the CYR61 gene, by administering doxorubicin” because You teaches that the CYR61 gene is involved in the pathogenesis of proliferative diabetic retinopathy, and that its expression levels are increased during retinal angiogenesis, i.e.[,] retinal neovascularization. Thus, it would have been obvious to measure the CYR61 levels before and after treatment as a means for determining whether or not the patient has active retinal angiogenesis. (Final Act. 5-6). The issue with respect to this rejection is: Does a preponderance of the evidence of record support the Examiner’s conclusion that Schulze and You render the claims obvious? Findings of Fact 1. Schulze teaches “treatment and/or diagnosis of ocular neovascularization diseases” (Schulze ¶ 43) where “‘[o]cular Appeal 2021-002304 Application 14/917,098 5 neovascularization diseases’ refers to diseases affecting the eye that are caused by or involve neovascularization, especially choroidal or [retinal] neovascularization. Examples of such diseases include, but are not limited to macular degeneration, especially wet age-related macular degeneration, retinopathy, especially proliferative diabetic retinopathy, and retinopathy of prematurity” (Schulze ¶ 83). 2. Schulze teaches the treatment method involves “selectively delivering at least one active agent to the angiogenic sites of neovascular ocular endothelium, comprising the use of a systemically administered cationic colloidal carrier preparation comprising at least one active agent” (Schulze ¶ 25). 3. Schulze teaches “the therapeutic agent is an antiangiogenic agent. Preferably, said antiangiogenic agent is . . . an anthracyclin preferably doxorubicin” (Schulze ¶ 101). 4. You teaches Cyr61, a member of the CCN family, induces endothelial cell proliferation and chemotaxis. Hypoxia induces the expression of Cyr61. Inhibition of the effect of Cyr61 reduces retinal neovascularization in a mouse model of OIR [oxygen-induced retinopathy]. Cyr61 is significantly expressed in the STZ- induced diabetic rat model. The concentration of Cyr61 is elevated in the vitreous of patients with PDR [proliferative diabetic retinopathy], especially those with active PDR. These results suggest that Cyr61 is involved in the pathogenesis of PDR and may be a useful target for PDR treatment. (You 3454, col. 2 to 3455, col. 1). 5. You teaches “[u]nder hypoxia, expression of Cyr61 mRNA and protein significantly increased. In the mouse OIR model, immunohistochemical studies showed Cyr61 expression in the neovascular Appeal 2021-002304 Application 14/917,098 6 tufts of the retina and retinal angiogenesis was inhibited by intravitreal injection of anti-Cyr61 antibody” (You 3453, col. 2). 6. Figure 6, panels A and B of You are reproduced in part below: FIGURE 6. Retinal expression of Cyr61 in STZ-induced diabetic rats. (A, B) Cyr61 and VEGF, in terms of mRNA (A) and protein levels (B), were significantly increased in the retina of STZ-induced rats when compared with control rats. The values of mRNA and protein expression were analyzed, using β-actin as the internal control. (You 3453, col. 1). 7. Figure 7, panel A of You is reproduced below: Appeal 2021-002304 Application 14/917,098 7 FIGURE 7. Vitreous levels of Cyr61 . . . and effects of immu- nodepletion of Cyr61 on chemotactic activity in RF/6A cells in vitreous samples from patients with PDR. . . . Note: average Cyr61 levels in the vitreous samples used in chemotaxis assay were 54.0 ± 17.5 ng/mL in the control group, 302.3 ± 74.4 ng/mL in the active PDR group, and 210.1 ± 93.2 ng/mL in the active PDR group vitreous pretreated with either rabbit IgG group or anti-Cyr61 antibody. (You 3454). 8. You teaches: “Cyr61 mRNA and protein expression in the retina increased in the diabetic animal model. Vitreous samples of patients with PDR had higher Cyr61 concentrations than did nondiabetic control subjects” (You 3453, col. 2). 9. Guadana teaches “oral delivery was studied as a possible noninvasive and patient preferred route to treat chronic retinal diseases as compared to injectable route” (Guadana 350, col. 2 to 351, col. 1). Principles of Law A prima facie case for obviousness “requires a suggestion of all limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003) and “a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Analysis We agree with Appellant that the evidence of record supports a finding that there would not have been a reasonable expectation of success in treating the patient population with PDR identified in You using the anthracycline anti-angiogenic agents like doxorubicin of Schulze. While the Appeal 2021-002304 Application 14/917,098 8 Examiner asserts that “patients suffering from proliferative diabetic retinopathy inherently have significantly higher levels of CYR61 expression compared to non-diseased individual” (Ans. 4; cf. FF 6-8), You’s Figure 7, panel A shows overlapping values between active and quiescent PDR and substantial overlap with the control values (FF 7). Appellant responds by rhetorically asking “would a patient having a CYR61 level of 90.0 ng/mL, for example, be said to have quiescent PDR or to not have PDR at all? One cannot make such a determination based on You’s CYR61 data” (Reply Br. 2). We agree that the prior art lacks sufficient disclosure to recognize that Cyr61 levels could be used as a reliable diagnostic for treatment. We also agree with Appellant that there is no reason to assume that reduction in Cyr61 levels would necessarily be associated with treatment of PDR. Even if it might be concluded that You teaches that Cyr61 levels are elevated in PDR (FF 4), that Cyr61 protein levels may be reduced using an antibody that also reduces neovascularization (FF 5) and suggests that Cyr61 may be a drug target for PDR (FF 4), You provides no basis to conclude that the mechanism of action of other compounds that may treat PDR such as the doxorubicin of Schulze would decrease activity of Cyr61. As Appellant points out “[e]ven if You recognized a potential role of CYR61 in retinal angiogenesis, what is there in Schulze that connects anthracyclines to CYR61 expression? There is, of course, absolutely nothing that does so” (Appeal Br. 4). We therefore agree with Appellant that this rejection relies on hindsight. “We must still be careful not to allow hindsight reconstruction of references to reach the claimed invention without any explanation as to how or why the references would be combined to produce the claimed Appeal 2021-002304 Application 14/917,098 9 invention.” Innogenetics, N.V. v. Abbott Labs., 512 F.3d 1363, 1374 n.3 (Fed. Cir. 2008). Conclusion of Law A preponderance of the evidence of record does not support the Examiner’s conclusion that Schulze and You render the claims obvious. DECISION SUMMARY In summary: In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 20, 21, 24 103 Schulze, You 20, 21, 24 1, 5, 17-19, 23 103 Schulze, You, Guadana 1, 5, 17-19, 23 Overall Outcome 1, 5, 17-21, 23, 24 REVERSED