GE HEALTHCARE LIMITED

Patent Trials and Appeals BoardJul 6, 2020

2020001210 (P.T.A.B. Jul. 6, 2020)

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. 15/742,512 01/07/2018 Christopher John Buckley 037380.00070 9734 157683 7590 07/06/2020 Arent Fox LLP and GE Healthcare 1717 K Street, NW Washington, DC 20006-5344 EXAMINER DONOHUE, SEAN R ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 07/06/2020 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): patentdocket@arentfox.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte CHRISTOPHER JOHN BUCKLEY and ADRIAN SMITH __________ Appeal 2020-001210 Application 15/742,5121 Technology Center 1600 __________ Before ERIC B. GRIMES, TAWEN CHANG, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method of staging beta amyloid pathology in a living human subject’s brain, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE Appellant’s Specification states that “[a]myloid is an abnormal deposit of insoluble protein fibrils in a body tissue or organ.” (Spec. 1) Beta amyloid (Aβ) is a specific type of amyloid involved in Alzheimer’s disease 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 GE Healthcare Limited. (Appeal Br. 2.) Appeal 2020-001210 Application 15/742,512 2 (AD). (Id.) “Aβ is one of the two neuropathological hallmarks of AD that can be seen microscopically in brain tissue specimens stained with certain dyes.” (Id.) “A number of positron emission tomography (PET) imaging agents that bind to Aβ are commercially-available.” (Id.) They “enable detection in living subjects of Aβ build up in plaques and in the blood vessels supplying the brain.” (Id. at 1–2.) “Thal . . . propose[d] five phases of Aβ amyloidosis (‘Thal phases’) based on histopathological assessment of post-mortem brain tissue.” (Id. at 2.) Appellant’s invention relates to in vivo imaging of Aβ plaques in the brain of a subject. Claims 1 and 4–19 are on appeal. Claims 1 and 17 are representative and read as follows: 1. A method for staging beta amyloid (Aβ) pathology in a living human subject’s brain wherein said method comprises: (i) administering an Aβ imaging agent to said subject such that the Aβ imaging agent is delivered to said subject’s brain; (ii) obtaining an in vivo image of said subject’s brain using a Aβ imaging agent; (iii) determining from said in vivo image the uptake of said Aβ imaging agent in a cortical region of said brain; and, (iv) determining from said in vivo image the uptake of said Aβ imaging agent in a striatal region of said brain; wherein positive uptake of said Aβ imaging agent in said cortical region and negative uptake of said Aβ imaging agent in said striatal region indicates Thal Phase 3 Aβ pathology and wherein positive uptake of said Aβ imaging agent in said cortical region and positive uptake of said Aβ imaging agent in said striatal region indicates Thal Phase 4 or 5 Aβ pathology. Appeal 2020-001210 Application 15/742,512 3 17. A method for treatment of Alzheimer’s disease (AD) wherein said method comprises the method as defined in Claim 1 and the further steps of: (v) selecting those subjects in whom Thal Phase 3 Aβ pathology or greater has been indicated; (vi) treating those subjects selected in step (v) with an AD therapy. (Appeal Br. Claims Appendix 1, 4.) The prior art relied upon by the Examiner is: Name Reference Date Shanka Vallabhajosula, Positron Emission Tomography Radiopharmaceuticals for Imaging Brain Beta-Amyloid, 41 Semin Nucl. Med. 283–99 (2011) Irina Alafuzoff et al., Assessment of β-amyloid deposits in human brain: a study of the BrainNet Europe Consortium, 117 Acta Neuropathol. 309–20 (2009) John C. Mazziotta, Mapping Human Brain Activity In Vivo, 161(3) West J. Med. 273–78 (1994) The following grounds of rejection by the Examiner are before us on review: Claims 1 and 4–17 under 35 U.S.C. § 103(a) as unpatentable over Alafuzoff and Vallabhajosula. Claims 1 and 4–19 under 35 U.S.C. § 103(a) as unpatentable over Alafuzoff, Vallabhajosula, and Mazziotta. DISCUSSION Claims 1 and 4–17 The Examiner finds that Alafuzoff teaches in vitro assessment of Aβ deposits in the human brain by staining brain samples with a monoclonal antibody directed against Aβ and obtaining images thereof. (See, e.g., Ans. Appeal 2020-001210 Application 15/742,512 4 7.) The Examiner further finds that Alafuzoff teaches that one can image regional involvement of amyloid in the brain in 10 anatomical regions (including cortical and striatal region) and determine the Aβ phase based on the regional binding. (Id. at 3, 7.) The Examiner finds that Alafuzoff teaches that 5 phases are known where phase 1 involves detection of Aβ binding to the monoclonal antibody in the neocortex; phase 2 involves binding detection in the neocortex and the allocortex; phase 3 involves binding detection in the neocortex, allocortex, and diencephalon as well as striatum; phase 4 involves binding detection in the neocortex, allocortex, diencephalon, striatum, and brainstem; and phase 5 involves binding detection in the neocortex, allocortex, diencephalon, striatum, brainstem, and cerebellum. (Id. at 3, 7.) The Examiner further finds that Alafuzoff teaches “that one may consider the rating of Aβ phases as a diagnostic tool while analyzing subjects with suspected Alzheimer’s disease (AD) (see pg. 310, col. 1).” (Id. at 3.) The Examiner finds that Vallabhajosula teaches PET radiopharmaceuticals for imaging Aβ in the brain, including 11C labeled PiB, and that such Aβ tracers “have the potential to become first-line imaging biomarker for diagnosis and staging of AD.” (Id. at 3–4.) The Examiner further finds that Vallabhajosula teaches the use of 11C labeled PiB-PET “to monitor treatment response to anti-Aβ immunotherapy with bapineuzumab (see pg. 296, Fig 15).” (Id. at 4.) Moreover, the Examiner finds that Vallabhajosula teaches that recent AD “Neuroimaging Initiative data indicate that FDG-PET [(18F-fluorodeoxyglucose-PET)] increased statistical power over traditional cognitive measures, might aid subject selection, and Appeal 2020-001210 Application 15/742,512 5 could substantially reduce sample size in clinical trials (see pg. 286, col. 2).” (Id.) In light of these teachings, the Examiner concludes that one of ordinary skill in the art would have found it obvious to modify the Alafuzoff method of staging Aβ to an in vivo method by using the PET imaging agents described in Vallabhajosula, obtain in vivo images of a subject’s brain, and determine from the images if there were uptake in the cortical and striatal regions. (Id. at 4–5.) The Examiner concludes such would have been obvious to “advantageously enable non-invasive staging of Aβ pathology in [a] living subject.” (Id. at 5.) The Examiner further concludes that it would have been obvious to select subjects with phase 3 Aβ pathology and treat them with an AD therapy “because it would advantageously enable halting downstream damage cause[d] by cerebral Aβ loads.” (Id.) We agree with the Examiner that the prior art relied upon supports finding claims 1 and 17 obvious. Claims 4–16 have not been argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). Appellant argues the Examiner’s rejection is in error because neither reference teaches both in vivo imaging and phase determination based thereon. (Appeal Br. 4–5; Reply Br. 2.) In particular, Appellant argues that Alafuzoff does not discuss how to conduct a phase “analysis on a living patient, or how one might adapt its teachings to an in vivo imaging technique.” (Appeal Br. 5.) Appellant then argues, even while acknowledging that Vallabhajosula “states ‘AB tracers for imaging have the potential to become a first-line imaging biomarker for diagnosing, and staging of AD.[’] See Vallabhajosula, p. 296,” that Vallabhajosula does not “teach[] comparing uptake of an imaging agent in different regions of the Appeal 2020-001210 Application 15/742,512 6 brain.” (Id.) Thus, according to Appellant, “because of the different and uncorrelated approaches of Alafuzoff and Vallabhajosula, the combined teachings do not suggest Applicant’s claimed solution.” (Id.) Appellant states “neither reference hints at examining uptake of an amyloid beta imaging agent in the cortex and the striatum to determine a subject’s specific Thal phase.” (Id.) We do not find Appellant’s arguments persuasive. One cannot defeat non-obviousness “by attacking the references individually[,] where the rejection is based upon the teachings of a combination of references.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (citation omitted). We agree with Appellant that Alafuzoff teaches assessment of Aβ pathology in post-mortem brain specimens and that Vallabhajosula teaches PET imaging in vivo using Aβ imaging agents. (Appeal Br. 4–5.) However, that does not end the obviousness inquiry. “In determining whether obviousness is established by combining the teachings of the prior art, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art.” In re GPAC Inc., 57 F.3d 1573, 1581 (Fed. Cir. 1995) (internal quotations omitted). We agree with the Examiner that the teachings of Alafuzoff and Vallabhajosula taken together would have rendered obvious the claimed invention to one of ordinary skill in the art. Alafuzoff teaches that “[i]n 2002, Thal and colleagues reported . . . a distinct pattern of involvement of brain regions with Aβ aggregates could be observed” in postmortem brains. (Alafuzoff 310.) Phase 3 involved the neocortex, allocortex, diencephalon and striatum, whereas phases prior to phase 3 did not involve diencephalon or striatum. (Id.) Phase 4 additionally Appeal 2020-001210 Application 15/742,512 7 involved the brainstem, and phase 5 additionally involved the cerebellum. (Id.) In other words, Alafuzoff teaches that it was known that there is a distinct pattern of regional brain involvement of Aβ aggregates in different phases of AD, and that there is “stepwise involvement” of the regions. (Id.; see also id. at 311 (“[T]he assessment of the distribution of Aβ aggregates in a subject with AD related tauopathy might be more than relevant since any alteration from the expected pattern may reflect a genetic alteration or the existence of a significant concomitant disease process”).) Vallabhajosula states “[d]ifferential diagnosis of dementia is very important.” (Vallabhajosula 296.) Vallabhajosula teaches several PET imaging agents that can be used as Aβ tracers in in vivo imaging of the brain. (See, e.g., id. at 288 (Table 1).) It is suggested that 11CPiB can be used in vivo to evaluate Aβ plaque burden in the cortex and striatum and that 18F-3’-F-PiB and 18F-AV-1 would perform similarly. (Id. at 289, 291–92; see also 294 (“[I]t was reported that significantly higher PiB retention was seen in the frontal, temporal, parietal, and occipital cortices; and the striatum of AD subjects compared with healthy controls.”).) In addition, Vallabhajosula states: In a proof-of-concept clinical study, 18F-BAY94-9172 PET scans showed potential utility in differential diagnosis of AD and FTLD [(frontotemporal lobar degeneration)] or healthy controls and might facilitate integration of Aβ imaging into clinical practice. (Id. at 292.) Vallabhajosula further states that: Florbetapir-PET imaging was correlated with the presence and density of Aβ, and the data provide evidence that a molecular imaging procedure can identify Aβ pathology in the brains of individuals during life. Appeal 2020-001210 Application 15/742,512 8 (Id.) This reference also states that, “[a]fter three decades, we have successfully developed several PET radiopharmaceuticals to image in vivo brain Aβ burden and regional distribution in patients with AD.” (Id. at 293 (emphasis added).) In short, Vallabhajosula provides evidence that PET Aβ tracers are known that can be imaged in various parts of the brain in vivo if there are Aβ plaques present. Furthermore, Vallabhajosula provides a reason that one would reasonably expect to be able to use the phase differentiation identified in Alafuzoff in conjunction with in vivo PET radiopharmaceuticals specific for Aβ because it suggests in vivo and post mortem staining are correlated. In particular, it is stated: The main brain regions showing PiB retention were the ventral prefrontal and posterior cingulate/precuneus cortices, following the known pattern of Aβ deposition as described in postmortem studies. The histologic and biochemical specificity of PiB binding across different regions of the AD brain was demonstrated by showing a direct correlation between Aβ- containing amyloid plaques and in vivo [11C]PiB retention measured by PET imaging. (Id. at 294 (emphasis added).) A similar study and finding was made with respect to 18F Florbetapir-PET. (Id. at 295.) Thus, for the foregoing reasons we find the Examiner has established the combined teachings suggest Appellant’s claimed invention, including comparing uptake in striatal regions and cortical regions. The only remaining question is whether the “wherein” clauses of the claim, which state certain determinations are indicative of certain Thal phase pathologies, distinguish the claimed method. “A ‘whereby’ clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim.” Texas Instruments, Inc. v. United Appeal 2020-001210 Application 15/742,512 9 States Int’l Trade Comm’n, 988 F.2d 1165, 1172 (Fed. Cir. 1993) (citation omitted); Minton v. Nat’l Ass’n of Sec. Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003) (“A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”) Here, the “wherein” clauses similarly merely state a possible observational outcome of the determination step, they do not state a condition of the process. Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329 (Fed. Cir. 2005) (“[W]hen the ‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.”).2 Consequently, we conclude these “wherein” clauses do not further limit the process set forth in steps (i)–(iv). Appellant separately argues claim 17, asserting that the references fail to teach the additional steps (v) and (vi) because they fail to teach performing steps (iii)–(iv) of claim 1. (Appeal Br. 7; Reply Br. 2–3.) However, for the reasons discussed above, we find that the combined references suggest steps (iii) and (iv). And in any event, we note that Vallabhajosula states “Aβ imaging can have a significant role in identifying 2 Moreover, the scope of the wherein clause regarding negative uptake of the Aβ imaging agent in the striatal region being indicative of Thal 3 is unclear. According to Alafuzoff, Thal phase 3 is defined as involving Aβ aggregates in the striatum that are detectable. (Alafuzoff at 310.) Appellant’s Specification indicates that a 50% of peak intensity compared to the thalamus and frontal white matter is indicative of a negative striatal scan. (Spec. 9.) This would suggest that uptake of the Aβ binding of the imaging agent in the striatal region may be present for Thal Phase 3 Aβ pathology. Such would be consistent with Alafuzoff’s discussion of the Thal Phase descriptions established in 2002 whereas a completely negative uptake would not be. Appeal 2020-001210 Application 15/742,512 10 patients at risk for AD who would be suitable candidates for anti-Aβ therapies.” (Vallabhajosula 297.) Thus, we conclude that claim 17 is suggested by the combination of Alafuzoff and Vallabhajosula. Claims 4–16 have not been argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). Claims 18 and 19 Claim 18 requires evaluation of the effects of an experimental AD therapy where the method comprises carrying out the method of claim 1 on subjects that are receiving experimental AD therapy. Vallabhajosula states “Aβ imaging might have a significant role in monitoring the efficacy of anti- Aβ therapies.” (Vallabhajosula 297.) The Examiner relies on Mazziotta for teaching the use of PET in the monitoring of experimental therapy. Ans. 5. We conclude that this reference is not even necessary to establish the claimed invention is prima facie obvious given the teaching of Vallabhajosula just discussed. Claim 19 recites a method to determine inclusion of subjects into a clinical trial where the method involves the steps of claim 1 and admission to clinical trial is based on positive uptake in the cortical region and negative uptake in the striatal region. As noted above, Vallabhajosula states “Aβ imaging can have a significant role in identifying patients at risk for AD who would be suitable candidates for anti-Aβ therapies.” (Vallabhajosula 297.) Furthermore, Vallabhajosula states that “[r]ecent Alzheimer’s Disease Neuroimaging Initiative (ADNI) data also indicate that FDG-PET increased statistical power over traditional cognitive measures, might aid subject selection, and could substantially reduce the sample size in a clinical trial.” Appeal 2020-001210 Application 15/742,512 11 (Id. at 286.) In combination with the reference teachings above, this statement suggests the claimed method for using the imaging and diagnostic phase determination for selecting a patient to enroll in a clinical study. Appellant’s only argument against the Examiner’s rejection of claims 18 and 19 is that Mazziotta does not disclose or suggest performing steps (iii)–(iv). (Appeal Br. 5–6.) However, as we discussed above, those steps are rendered obvious by the combination of Alafuzoff and Vallabhajosula. In affirming a multiple reference rejection under 35 U.S.C. § 103, the Board may rely on fewer than all of the references relied on by the Examiner in an obviousness rationale without designating it as a new ground of rejection. In re Bush, 296 F.2d 491, 496 (CCPA 1961). DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 4–17 103 Alafuzoff, Vallabhajosula 1, 4–17 1, 4–19 103 Alafuzoff, Vallabhajosula, Mazziotta 1, 4–19 Overall Outcome 1, 4–19 Appeal 2020-001210 Application 15/742,512 12 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED