CTNF 18/417,787 CTNF 96502 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 07-06 AIA 15-10-15 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 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. Priority The instant application, filed 01/19/2024, is a continuation of PCT/US2022/074007, filed 07/21/2022, and claims domestic benefit to US provisional applications 63/227,895, filed 07/30/2021, and 63/224,848, filed 07/22/2021. Status of Claims/Application Applicant’s preliminary amendment of 04/04/2024 is acknowledged. Claims 10, 15, 28, 43, 50, 63-64, 66, 68, 70, and 72 are amended and claims 2-9, 11-14, 16-27, 29-42, 45-49, 51-62, 65, 67, 69, 71, and 73-137 are cancelled. Claims 1, 10, 15, 28, 43-44, 50, 63-64, 66, 68, 70, and 72 are currently pending and are examined on the merits herein. Information Disclosure Statement The information disclosure statements (IDS) submitted on 01/19/2024 and 12/29/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner. Claim Objections Claim 63 is objected to because of the following informalities: the instant claim recites the limitation “an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3” in line 4. The instant disclosure defines SEQ ID NO: 3 as being the amino acid sequence “GDY” (pg. 163); however, because the sequence is less than four amino acids in length, it cannot be included in the sequence listing. See MPEP 2417. As such, SEQ ID NO: 3 in the sequence listing is blank. It is suggested that the reference to “SEQ ID NO: 3” in the claim be amended to the recite the sequence “GDY” since SEQ ID NO: 3 is empty in the sequence listing. Claim Rejections - 35 USC § 112(a) 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 Claims 1, 10, 15, 28, 43-44, 50, 70, and 72 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Independent claim 1 is drawn to methods for treating Alzheimer’s disease in a subject comprising subcutaneous administration of a composition comprising a brain targeting antibody or antigen-binding fragment thereof, wherein the antibody or fragment is at a concentration of about 130 mg/mL to about 200 mg/mL. Independent claims 70 and 72 are drawn to a method for treating Alzheimer’s disease in a subject comprising subcutaneously administering to the subject a first and second dose, as recited in the claims, of a brain targeting antibody or an antigen binding fragment thereof. The claims are drawn to a genus of antibodies or antigen binding fragments, specifically any that target the brain, and claims the antibodies/binding fragments with the functional limitation of treating Alzheimer’s disease. The instant disclosure, however, does not demonstrate a representative number of species of the claimed genus performing the claimed function, nor does the disclosure identify a structure function relationship that would allow an ordinarily skilled artisan to predictably identify which brain targeting antibodies, or fragments thereof, would be capable of performing the claimed function(s). The examples of the instant disclosure detail a phase I study assessing the safety and tolerability of single ascending volumes of subcutaneously administered placebo and of single ascending doses of subcutaneously administered crenezumab. A formulation of crenezumab of 150 mg/mL was used in cohorts A-D and 180 mg/mL in cohorts E-H. The formulation comprised succinic acid, L-arginine, and polysorbate 20. Infusions were delivered at a flow rate of approximately 1 mL/min (pages 164-165, Example 1). Example 2, starting on page 168, provides a study of safety and tolerability of different combinations of crenezumab with or without rHuPH20, infusion volume, and flow rates. Example 3, on pages 173-174, studied crenezumab preparation, viscosity, and stability. In both examples 1 and 2, in which crenezumab was administered to subjects, studies were performed using healthy subjects. The examples of the instant disclosure studied only a single brain targeting antibody, namely crenezumab, and do not appear to experimentally demonstrate the treatment of Alzheimer’s with crenezumab at the concentrations/regimens recited in the instant claims. The disclosure also contemplates other anti-Aβ antibodies as brain targeting antibodies including solanezumab, bapinezumab, aducanumab, and gantenerumab (page 24, [0100]). The disclosure does not demonstrate any of these antibodies in methods of treating Alzheimer’s disease using the recited methods. The anti-Aβ antibodies demonstrated and considered by applicant, however, are not representative of the entire scope of the instantly claimed genus in which any brain targeting antibody is claimed, limited by the recited concentrations and/or dosages and/or administration regimen, with the function of treating Alzheimer’s. The prior art also does not support the full scope of the instantly claimed genus nor does the art provide a structure-function relationship that would allow an ordinarily skilled artisan to predictably identify which brain targeting antibodies in the claimed methods would successfully treat Alzheimer’s disease in a subject. The teachings of Courade, J.P., et al (2025) The evolving landscape of Alzheimer’s disease therapy: From Aβ to tau Cell 188; 7337-7354 , US 2019/0010238 A1 (Wisniewski, T., et al) 10 Jan 2019 and WO 2018/231254 A1 (Tirucherai, G., et al) 20 Dec 2018 demonstrate that the genus of antibodies encompassed by the claim to brain targeting antibodies or antigen binding fragments thereof comprises antibodies in addition to the anti-Aβ antibodies considered in the instant disclosure. The art also demonstrates unpredictability in identifying which brain targeting antibodies (structure) would be capable of treating Alzheimer’s disease in the instantly claimed methods (function). For instance, Courade teaches that recent breakthroughs have opened a new era in Alzheimer’s disease research and treatment. These include the recent US FDA approvals of anti-Aβ therapies- lecanemab and donanemab- resulting from decades of setbacks yielding incremental success in Aβ antibody trial optimization. Emerging outcomes of tau trials are fast following the Aβ successes, showing slower tau accumulation and early signs of cognitive benefits. While primary endpoints have not been met, and corroboration in multiple, large, future trials will be critical, these outcomes represent first proof of concept in humans of biological disease halting and present an important step forward for tau therapeutic agents (page 7337, left column, paragraph 1). Courade teaches that both Aβ and tau represent key therapeutic targets and accumulating evidence supports an initiatory role for Aβ in AD, while tau is proposed to have an executive role in the neurodegenerative process downstream of Aβ, including Aβ-independent roles. Indeed, tau pathology closely correlates with symptom progression (paragraph bridging pages 7337-7338). Courade teaches a multitude of anti-tau antibodies that have been developed, or are being developed, that target various Tau epitopes (page 7342, Fig. 3). Courade teaches that the Alzheimer’s field has thus moved beyond the binary view of ‘‘Aβ versus tau.’’ Tau and Aβ are interacting drivers within a broader neurodegenerative cascade of events, demanding multi-modal and mechanism driven, disease-modifying therapies. Courade also acknowledges that, at the time of publication, no current treatment can yet sufficiently halt disease progression for patients, and that many important challenges remain (page 7348, left column, paragraphs 3-4). US’238 teaches anti-prion monoclonal antibodies and their use for the treatment of conditions associated with or mediated by proteins and peptides having a toxic oligomeric form. These conditions include Alzheimer’s disease (abstract). US’238 teaches that neurofibrillary tangles (NFTs) are a hallmark lesion in Alzheimer’s disease and are composed mainly of paired helical filaments (PHF), which have a hyperphosphorylated form of the microtubule associated protein tau as the major component. A hyperphosphorylation and associated aggregation/oligomerization is thought to be a critical event linked to microtubule disorganization, and the subsequent generation of neurofibrillary tangles which are associated with neuronal toxicity, dysfunction, and synaptic loss. Numerous studies have been performed to gain a better understanding of the role of aggregated Aβ species on AD pathology; however, recently there has been much more focus on tau related pathology with the published failure of several amyloid β targeted therapeutic approaches in phase III clinical trials (page 1, [0004]). US’238 suggests formulations comprising about 0.1 mg/mL to about 50 mg/mL of the antibody (page 10, [0085]). WO’254 teaches dosage regimens and formulations of anti-human tau antibodies and their use in the treatment of tauopathies such as Alzheimer’s disease (abstract). WO’254 teaches that protein accumulation, modifications, and aggregation are pathological aspects of numerous neurodegenerative diseases. Pathologically modified and aggregated tau including hyperphosphorylated tau conformers are an invariant hallmark of tauopathies and correlate with disease severity. The microtubule associated protein tau is abundant in the central nervous system and produced by neurons. Tau promotes assembly of, maintains the structures of, and stabilizes microtubules. Tauopathies are a class of neurodegenerative diseases resulting from the pathological aggregation of Tau protein into so called neurofibrillary tangles (NFT) in the brain (page 1, background). WO’254 suggests anti-human tau antibody formulations comprising 10 mg/mL, 60 mg/mL, or 50 mg/mL (page 15, paragraph 3). Courade, US’238, and WO’254 teach brain targeting antibodies with targets outside of the Aβ target considered by the instant disclosure for use in the claimed methods demonstrating the scope of the claimed invention. The instant disclosure does not contemplate alternative brain targeting antibodies, such as anti-tau or anti-prion antibodies, nor does the instant disclosure demonstrate that the antibodies would be effective in the instantly claimed methods. While Courade, US’238, and WO’254 provide species of brain targeting antibodies that could be used to treat Alzheimer’s, the references do not demonstrate the use of the antibodies in the instantly claimed methods with the recited concentrations/regimens, and also do not provide a structure-function relationship that would help to predictably identify which brain targeting antibodies would be capable of treating Alzheimer’s disease when used in the instantly claimed methods. Additionally, Courade suggests unpredictability in the art and demonstrates the need for optimization of methods in order to achieve successful treatment of Alzheimer’s disease. The prior art also suggests that even antibodies targeting Aβ are unpredictable in the treatment of Alzheimer’s disease. For instance, Prins, N.D., and P. Scheltens (2013) Treating Alzheimer’s disease with monoclonal antibodies: current status and outlook for the future Alzheimer’s Research & Therapy 5(56); 1-6 teaches that in the past decade, Alzheimer’s disease drug discovery had been directed at disease modifying drugs. At the time of publication, results from two large phase 3 trial programs with bapineuzumab and solanezumab, respectively, had brought rather disappoint results. Possible explanations provided include that the compounds were either targeting the wrong amyloid-β species, or were given too late in the disease process (abstract). Prins provides an overview of monoclonal antibodies that were being tested for the treatment of Alzheimer’s disease in table 1 on page 3, which all target Aβ. Prins also provides what epitope of Aβ the antibodies target as well as the trial results. The results demonstrate that some of the antibodies showed reduction in brain amyloid beta and that the mAbs were safe and well tolerated, while others, such as bapineuzumab and solanezumab, did not meet cognitive and functional endpoints. The teachings of Prins demonstrates that, even antibodies having the same general target, such as Aβ, do not all demonstrate clinical efficacy suggesting that the structure and function relationship between brain targeting antibodies and the treatment of Alzheimer’s was not predictable. Neither the instant disclosure, nor the art, provide a representative number of species of the instantly claimed genus performing the claimed function of treating Alzheimer’s disease when implemented in the claimed methods. The instant disclosure and art also do not describe a structure-function correlation that would allow for the predictable identification of which brain targeting antibodies would be capable of treating Alzheimer’s disease when used in the claimed methods. Rather the art suggests that the use of brain targeting antibodies in the treatment of Alzheimer’s disease was not predictable. Therefore, the instant claims were found not to meet the written description requirements of 35 USC 112(a). Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/040612 A1 (Lantz, S.A., et al) 28 Feb 2019 . WO’612 teaches pharmaceutical compositions containing anti-beta amyloid (Aβ) antibodies or Aβ-binding fragments thereof. The pharmaceutical compositions find use in the treatment of abnormal accumulation or deposition of Aβ in the central nervous system, mild cognitive impairment, and Aβ-associated disorders, such as Alzheimer’s disease (abstract). WO’612 teaches that AD patients having high serum titers of anti-Aβ antibodies that recognize amyloid plaques have slower rates of cognitive decline and disability compared to patients that do not have anti-Aβ antibodies. Moreover, patients who develop high titers of anti-Aβ antibodies show reduced number of brain Aβ plaques and improved cognitive performance assessed after long-term follow up (page 1, background, paragraph 2). WO’612 teaches that the anti-Aβ antibody, BIIB037 (Aducanumab), is a fully human antibody comprising a glycosylated human IgG1 heavy chain and a human kappa light chain. Recombinantly expressed BIIB037 binds with high apparent affinity to high molecular weight aggregates, presumably fibrils, of human Aβ. By immunohistochemistry, BIIB037 shows high affinity binding to Aβ plaques in human AD brain and in brain tissues derived from human APP-expressing transgenic mice. The affinity and specificity of BIIB037 for high molecular weight aggregates of human Aβ was confirmed by immunoprecipitation, immunoblotting, and immunohistochemistry. In Tg2576 AD transgenic mice, BIIB037 treatment results in measurable drug levels in the brain as assessed by ELISA. Following administration of BIIB037 in Tg2576 mice, immunoreactivity for BIIB037 was observed in association with brain parenchymal and vascular amyloid deposits, suggesting that BIIB037 enters brain parenchyma and binds to its target. It is believed that systemically administered anti-Aβ antibodies, such as BIIB037, enter the brain, bind to deposits of Aβ and trigger their clearance from the brain by Fc receptor dependent mechanisms. Antibody-mediated removal of Aβ from the brain is hypothesized to decrease Aβ burden, thereby preventing neuronal dysfunction, slowing the progression of pathology and reducing the rate of cognitive decline in AD (paragraph bridging pages 1-2). WO’612 teaches pharmaceutical compositions comprising anti-Aβ antibody or Aβ-binding fragments thereof and teaches that the compositions comprise the anti-Aβ antibody or Aβ-binding fragment thereof at a concentration of 50 mg/mL to 250 mg/mL or 75 mg/mL to 165 mg/mL. WO’612 also teaches that, in certain embodiments, the composition comprises the anti-Aβ antibody or binding fragment thereof at a concentration of 150 mg/mL (page 2, last paragraph). WO’612 also exemplifies compositions of Aducanumab (BIIB037) at concentrations of 165 mg/mL (page 37, Example 6), 200 mg/mL (page 38, Example 9), and 150 mg/mL (pXDage 39, Example 13). WO’612 also performed a 4-week tolerability and toxicokinetic study of BIIB037 when administered intravenously or subcutaneously at a concentration of 150 mg/mL (page 39, example 13). WO’612 teaches anti-Aβ antibody or binding fragments thereof at concentrations that overlap with (50-250 mg/mL) or lie inside of (165, 200, and 150 mg/mL) the claimed ranges rendering the claimed ranges obvious as it would be obvious to use any of these concentrations in the anti-Aβ antibody compositions with a reasonable expectation of success. See MPEP 2144.05. WO’612 further teaches that the compositions disclosed are useful in treating abnormal accumulation or deposition of Aβ in the central nervous system of a human subject in need thereof. The compositions are useful in treating Alzheimer’s disease in a human subject in need thereof. A human subject in need thereof is administered a therapeutically effective amount or dose of the antibody or binding fragment thereof. A therapeutically effective amount refers to the amount of the antibody sufficient to ameliorate a symptom or condition associated with AD (page 32, methods of treatment). WO’612 further teaches subcutaneous administration of the composition to a human subject (page 33, paragraph 2). While WO’612 does not exemplify the treatment of Alzheimer’s disease using the disclosed compositions and methods, the treatment of Alzheimer’s disease would have been obvious with a reasonable expectation of success based on the teachings of WO’612 as a whole. Specifically, WO’612 teaches that the compositions disclosed can be used to treat Alzheimer’s disease via subcutaneous administration and teaches that systemically administered anti-Aβ antibodies, such as BIIB037, can enter the brain, bind to deposits of Aβ, and trigger their clearance from the brain decreasing Aβ burden; thereby preventing neuronal dysfunction, slowing the progression of pathology and reducing the rate of cognitive decline in AD. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success . 07-21-aia AIA Claim s 1, 10, 15, 28, 43-44, 63-66, and 68 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0016791 A1 (Smith, J., et al) 17 Jan 2019 in view of WO 2019/040612 A1 (Lantz, S.A., et al) 28 Feb 2019 . US’791 teaches methods of treating Alzheimer’s disease (AD) in patients suffering from early AD, including amyloid positive patients, ApoE4 positive patients, and patient suffering from prodromal or mild AD (abstract). US’791 teaches that crenezumab, also known as MABT5102A, is a fully humanized IgG4 monoclonal antibody to Abeta selected for its ability to bind both monomeric and oligomeric forms of Abeta in vitro. Crenezumab binds both Abeta1-40 and Abeta1-42, inhibits Abeta aggregation, and promotes Abeta disaggregation. Because crenezumab is a human IgG4 backbone antibody, it has reduced Fcγ receptor binding affinity compared with human IgG1 or IgG2, which is predictive of reduced immune effector response. These properties, combined with the ability of systemically delivered crenezumab to decrease Abeta CNS levels in a murine model of AD, have suggested that this anti-Abeta therapeutic approach may offer clinical efficacy while having a lower risk of the potentially deleterious side effects, such as ARIA-E or cerebral vasogenic edema, or hemorrhages, which have been seen in clinical trials of other Abeta antibody therapies (page 2, [0009]). The results of pre-clinical and clinical studies in AD patients have demonstrated that crenezumab can be administered at high dosages without triggering dose-limiting adverse events (page 2, [0010]). Consequently, US’791 discloses methods of treating patients suffering from AD and other amyloidosis comprising administering a humanized monoclonal antibody or antigen binding fragments thereof, at doses of 2 grams or more (page 2, [0011]). US’791 teaches that the antibody comprises heavy and light chain variable regions having the amino acid sequence of SEQ ID NOs: 10 and 11, respectively (page 2, [0011]) and teaches that the antibody is crenezumab. US’791 SEQ ID NOs: 10 and 11 are identical to instant SEQ ID NOs: 7 and 8, respectively, as shown in the alignments below. The sequences disclosed by US’791 also comprise the HVR-H1-3 and HVR-L1-3 of instant claim 63, which are annotated in the alignments with an underline. PNG media_image1.png 347 969 media_image1.png Greyscale PNG media_image2.png 342 968 media_image2.png Greyscale US’791 teaches that suitable dosages are multi-gram dosages and can range from about 1500 mg to about 24000 mg (page 3, [0014]). In certain embodiments, the antibody is administered as a flat dose of 1500mg, 1800mg, 2000mg, 2400mg, 3000mg, 3200mg, 4000mg, 5000mg, 5400mg, 6000mg, 7000mg, 7200mg, 8000mg, or higher. In some embodiments, the dose is administered by subcutaneous injection every 2 or every 4 weeks for a period of time. In certain embodiments, the period of time is 6 months, one year, eighteen months, two years, five years, ten years, 15 years, 20 years, or the lifetime of the patient (page 21, [0213]). The dosages disclosed by US’791 overlap with (1500-24000mg) and lie inside of (1500mg, 1800mg, 2000mg, 2400mg, 3000mg, 3200mg, 4000mg, 5000mg, 5400mg, 6000mg, 7000mg, 7200mg) the range claimed in instant claim 15, rendering the instantly claimed range obvious as it would have been obvious to use any of the dosages disclosed by US’791 with a reasonable expectation of success. See MPEP 2144.05. US’791 further teaches pharmaceutical compositions comprising the anti-Abeta antibody disclosed with one or more optional pharmaceutically acceptable carrier. US’791 also teaches that acceptable carriers include interstitial drug dispersion agents, such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (page 19, [0194]). rHuPH20 meets the instant claims 43-44 limitations of a permeation enhancer and a recombinant human hyaluronidase as evidenced by the instant specification, which identifies rHuPH20 as a recombinant human hyaluronidase ([0051]). US’791, however, does not disclose that the anti-Abeta antibody is at a concentration of about 130 mg/mL to 200 mg/mL as is instantly claimed. The teachings of WO’612 are as discussed in detail above. It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by US’791 by having the anti-Abeta antibody or binding fragment thereof in a composition comprising 50 mg/mL to 250 mg/mL, including 150 mg/mL, 165 mg/mL, or 200 mg/mL, of antibody or antigen binding fragment as disclosed by WO’612. It would have been obvious to an ordinarily skilled artisan to have the anti-Abeta antibody or binding fragment thereof in a composition with the concentrations of WO’612 as WO’612 demonstrates that such concentrations had been considered for compositions of anti-Abeta antibodies or fragments thereof for use in methods of treating Abeta associated disorders such as Alzheimer’s disease. Additionally, both US’791 and WO’612 teach that the compositions disclosed can be administered subcutaneously, demonstrating that compositions with the concentrations disclosed in WO’612 had been considered for use in the same administration route disclosed by US’791. Regarding claim 28, as discussed in detail above, US’791 teaches dosages of anti-Abeta antibody of 1500-24000mg and WO’612 teaches anti-Abeta antibody concentrations including, for instance, 150 mg/mL, 165 mg/mL, and 200 mg/mL. Administering the anti-Abeta antibody at the dosages disclosed by US’791 using the composition concentrations disclosed by WO’612 would require the following infusion volumes: 1500-24000 mg with 150 mg/mL composition: 10 mL – 160 mL 1500-24000 mg with 165 mg/mL composition: 9 mL – 145 mL 1500-24000 mg with 200 mg/mL composition: 7.5 mL – 120 mL The volumes required to deliver the dosages disclosed by US’791 with the composition concentrations disclosed by WO’612 overlap with the instantly claimed infusion volume of about 4 – about 60 mL, rendering the instantly claimed range obvious as it would have been obvious to one of ordinary skill in the art to use an infusion volume within the ranges suggested by the combination of US’791 and WO’612 to provide the subject with the appropriate and desired dosage of the anti-Abeta antibody in the methods disclosed by US’791. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’791 and WO’612 both teach methods of subcutaneous administration of anti-Abeta antibodies for the treatment of Alzheimer’s disease. Regarding claim 66, as discussed above, US’791 teaches that the anti-Abeta antibody is crenezumab, which the instant disclosure identifies as comprising instant SEQ ID NOs: 9 and 10 (page 24, [0101]). US’791, however, teaches that the anti-Abeta antibody comprises a heavy and light chain of SEQ ID NOs: 5 and 9, respectively. US’791, SEQ ID NOs: 5 and 9 have the following alignment with instant SEQ ID NOs: 9 and 10, respectively: PNG media_image3.png 704 617 media_image3.png Greyscale PNG media_image4.png 387 615 media_image4.png Greyscale As shown in the alignments, the light chain taught by US’791 is identical to instant SEQ ID NO: 10. The heavy chain, however, differs from instantly claimed SEQ ID NO: 9 in that the instantly claimed sequence comprises a C-terminal lysine (K). US’791 further teaches that the C-terminal lysine in the Fc region of the heavy chain may or may not be present (page 10, [0092]). It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the heavy chain of the anti-Abeta antibody disclosed by US’791 by further including a C-terminal lysine on the heavy chain as taught by US’791. It would have been obvious to include the C-terminal lysine with a reasonable expectation of success as US’791 teaches that the IgG heavy chain Fc region may or may not comprise the C-terminal lysine . 07-21-aia AIA Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0016791 A1 (Smith, J., et al) 17 Jan 2019 in view of WO 2019/040612 A1 (Lantz, S.A., et al) 28 Feb 2019 as applied to claims 1, 43, and 44 above, and in further view of Locke, K.W., et al (2019) ENHANZE® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20 Drug Delivery 26(1); 98-106 . The combination of US’791 and WO’612 teach the method of claim 44 as discussed in detail above. As discussed above, US’791 teaches that the composition administered to the subject further comprises rHuPH20 (page 19, [0194]), which is a recombinant human hyaluronidase. The combination of applied references, however, does not disclose that the concentration of the rHuPH20 is about 400 U/mL to about 2000 U/mL as recited in instant claim 50. Locke teaches a drug delivery technology using a proprietary recombinant human hyaluronidase PH20 (rHuPH20) to facilitate the subcutaneous delivery of co-administered therapies. rHuPH20 works by locally degrading hyaluronan (HA), a large glycosaminoglycan and component of extracellular, pericellular, and intracellular matrices. Hyaluronan is a key component of the skin that forma gel-like substance with water, creating resistance to bulk fluid flow and limiting large volume SC drug delivery, dispersion, and absorption (page 98, left column, paragraph 1). rHuPH20 specifically has been shown to facilitate SC bulk fluid flow and to increase the dispersion and absorption of co-administered therapeutics. rHuPH20 can enable intravenously administered therapies to be given subcutaneously and permits larger SC administration volumes that can reduce the number and potential frequency of individual injections required. Furthermore, clinical trials have shown that rHuPH20 has the potential to improve pharmacokinetic (PK) profiles of co-administered SC agents compared with SC administration without rHuPH20; it can potentially increase the absorption rate, increase bioavailability, increase maximum plasma concentrations, accelerate time to reach maximum concentration, and decrease intra-individual variability in PKs (paragraph bridging columns, page 98). Locke teaches that rHuPH20’s mechanism of action has been demonstrated in a number of preclinical studies using immunoglobulin G (IgG) as a representative therapeutic protein. These studies, in which minipigs were used as a model for human skin, confirmed that SC delivery of rHuPH20 increased dispersion and absorption of large volumes of co-administered therapeutic proteins. Compared with control infusions, rHuPH20 significantly reduced infusion pressure and induration and accelerated proinfusion IgG dispersion (page 99, right column, paragraph 2). Locke teaches that, according to the US prescribing information, HYLENEX recombinant 150 U can be injected prior to the start of subcutaneous fluid administration to facilitate absorption of 1000 mL or more of solution. The dose, rate of injection, and type of solution need to be adjusted on an individual basis (page 99, right column, paragraph 1). These teachings of Locke suggest that doses as low as 150 U/1000 mL of solution, or 0.150 U/mL can be effective in increasing absorption. Locke provides a review of the application of rHuPH20 in marketed products including antibodies (page 100, Application of rHuPH20 in marketed products). Locke teaches the inclusion of 2000 U/mL rHuPH20 in antibody formulations for subcutaneous administration. For instance, Locke teaches that Herceptin SC combines rHuPH20 and trastuzumab, a monoclonal antibody targeting HER2. The combination comprises 2000 U/mL of rHuPH20 and 600 mg/5mL of trastuzumab and is approved for SC administration of the treatment of HER2 positive cancers (page 101, right column, last paragraph). Locke also teaches compositions comprising rituximab, an anti-CD20 antibody, at doses of 1400 mg/11.7mL or 1600 mg/13.4 mL combined with 2000 U/mL of rHuPH20 (page 102, right column, paragraph 4). It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by the combination of US’791 and WO’612 to include 2000 U/mL of rHuPH20 as disclosed by Locke. An ordinarily skilled artisan would have been motivated to include 2000 U/mL of rHuPH20 as Locke teaches numerous benefits of including rHuPH20 in subcutaneous formulations and teaches antibody formulations comprising 2000 U/mL of rHuPH20. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’791 and Locke teach the inclusion of rHuPH20 in antibody formulations for subcutaneous administration . 07-21-aia AIA Claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0016791 A1 (Smith, J., et al) 17 Jan 2019 in view of WO 2019/040612 A1 (Lantz, S.A., et al) 28 Feb 2019 and Bittner, B., et al (2018) Subcutaneous administration of biotherapeutics: an overview of current challenges and opportunities BioDrugs 32; 425-440 . The teachings of US’791 are as discussed in detail above. As discussed above, US’791 teaches methods of treating Alzheimer’s disease in a subject comprising subcutaneous administration of the anti-Aβ antibody, crenezumab. US’791 also teaches antibody dosages ranging from about 1500 mg to about 24000 mg, including flat doses of 1500mg, 1800mg, 2000mg, 2400mg, 3000mg, 3200mg, 4000mg, 5000mg, 5400mg, 6000mg, 7000mg, 7200mg, and 8000mg (page 3, [0014]; page 21, [0213]). US’791 also teaches that the dose is administered by subcutaneous injection every 2 to 4 weeks for a period of time (page 21, [0213]), indicating multiple dosages. The dosages disclosed by US’791 encompass the instantly claimed dosages of 1700 and 3400 mg. US’791; however, does not disclose the instantly claimed regimen. The teachings of WO’612 are as discussed in detail above. As discussed in detail above, WO’612 teaches anti-Aβ antibody concentrations including, for instance, 150 mg/mL, 165 mg/mL, and 200 mg/mL. As discussed above, the combination of the doses of US’791 and the composition concentrations of WO’612 suggest infusion volumes of between 7.5 mL and 160 mL. Bittner teaches that subcutaneous delivery of biotherapeutics has become a valuable alternative to intravenous administration across many diseases. Bittner discusses differences between subcutaneous and intravenous dosing from both health-economic and scientific perspectives covering differences in indications, treatment settings, administration volumes, and injection devices (abstract). Bittner teaches injection volumes ranging from 0.4 mL up to 50 mL (page 427, table 1; page 428, left column). Bittner also teaches that infusion pumps facilitate high-volume subcutaneous infusions with 3-20 mL typically administered over 5-20 minutes, as well as the use of the so-called rapid push subcutaneous administration that allows for delivery over shorter intervals, e.g., less than 5 minutes (page 432, left column, paragraph 2). The infusion of 3-20 mL administered over 5-20 minutes suggests an infusion rate of between 0.15 ml/min (3ml/20min) to 4 ml/min (20ml/5min). It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to subcutaneously administer the crenezumab antibody in the methods disclosed by US’791 using the methods disclosed by WO’612 and Bittner and to use optimization that was routine in the art to determine the optimal dose, volume, and flow rate for administration of the antibody. It would have been obvious to use the methods disclosed by WO’612 and Bittner as WO’612 demonstrates that high concentration formulations of anti-Aβ antibodies had been studied in the art and Bittner teaches methods for the subcutaneous administration of antibodies. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. It would have further been obvious to use the teachings of US’791, WO’612, and Bittner as a starting point for routine optimization in order to identify the optimal dose, infusion volume, and flow rate for subcutaneous administration of crenezumab for the treatment of Alzheimer’s disease. MPEP 2144.05 (II) A. states "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. In this case, US’791 teaches dosage ranges that encompass those of the instant claim and also teaches that the appropriate dosage of antibody will depend on the severity and course of disease, previous therapy, the patient’s clinical history and response to the antibody, and the discretion of the attending physician (page 21, [0212]). US’791 also demonstrates that serum concentration of crenezumab is a function of the dose, demonstrating that the dose of antibody was considered to be a result effective variable. Bittner demonstrates that infusion volumes and infusion rates encompassing those of the instant claim were also known in the art for subcutaneous administration and suggests that the treatment can be according to the individual patient’s comfort level and the addition of additional therapeutics, such as rHuPH20. One of ordinary skill in the art would also reasonably recognize that the infusion volume and time is a result effective variable that will depend on the dose that is given and concentration of the antibody in the composition administered. In this regard it is noted that, as discussed above, WO’612 demonstrates high concentration compositions of anti-Aβ antibodies which, when given at the dosages taught by US’791, encompass the volumes taught by Bittner as possible for subcutaneous infusion. Therefore, one of ordinary skill in the art could use the teachings of US’791, WO’612, and Bittner as a starting point for routine optimization to arrive at the instantly claimed regimen . 07-21-aia AIA Claim 72 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0016791 A1 (Smith, J., et al) 17 Jan 2019 in view of WO 2019/040612 A1 (Lantz, S.A., et al) 28 Feb 2019 , Bittner, B., et al (2018) Subcutaneous administration of biotherapeutics: an overview of current challenges and opportunities BioDrugs 32; 425-440 , and Locke, K.W., et al (2019) ENHANZE® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20 Drug Delivery 26(1); 98-106 . The teachings of US’791 are as discussed in detail above. As discussed above, US’791 teaches methods of treating Alzheimer’s disease in a subject comprising subcutaneous administration of the anti-Aβ antibody, crenezumab. US’791 also teaches antibody dosages ranging from about 1500 mg to about 24000 mg, including flat doses of 1500mg, 1800mg, 2000mg, 2400mg, 3000mg, 3200mg, 4000mg, 5000mg, 5400mg, 6000mg, 7000mg, 7200mg, and 8000mg (page 3, [0014]; page 21, [0213]). US’791 also teaches that the dose is administered by subcutaneous injection every 2 to 4 weeks for a period of time (page 21, [0213]), indicating multiple dosages. The dosages disclosed by US’791 encompass the instantly claimed dosages of 1700 and 3400 mg. US’791; however, does not disclose the instantly claimed regimen. The teachings of WO’612 are as discussed in detail above. As discussed in detail above, WO’612 teaches anti-Aβ antibody concentrations including, for instance, 150 mg/mL, 165 mg/mL, and 200 mg/mL. As discussed above, the combination of the doses of US’791 and the composition concentrations of WO’612 suggest infusion volumes of between 7.5 mL and 160 mL. The teachings of Bittner are as discussed above. As discussed in detail above, Bittner teaches injection volumes ranging from 0.4 mL up to 50 mL (page 427, table 1; page 428, left column). Bittner also teaches that infusion pumps facilitate high-volume subcutaneous infusions with 3-20 mL typically administered over 5-20 minutes, as well as the use of the so-called rapid push subcutaneous administration that allows for delivery over shorter intervals, e.g., less than 5 minutes (page 432, left column, paragraph 2). The infusion of 3-20 mL administered over 5-20 minutes suggests an infusion rate of between 0.15 ml/min (3ml/20min) to 4 ml/min (20ml/5min). The teachings of Locke are as discussed in detail above and suggest rHuPH20 concentrations ranging from 0.150 U/mL up to 2000 U/mL can be effective in facilitating subcutaneous therapeutic administration, including antibody administration. It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to subcutaneously administer the crenezumab antibody in the methods disclosed by US’791 using the methods disclosed by WO’612 and Bittner and to further include rHuPH20 at the concentrations disclosed by Locke. It would also have been obvious to use optimization that was routine in the art to determine the optimal dose, volume, and flow rate for administration of the antibody and the concentration of the rHuPH20. It would have been obvious to use the methods disclosed by WO’612 and Bittner as WO’612 demonstrates that high concentration formulations of anti-Aβ antibodies had been studied in the art and Bittner teaches methods for the subcutaneous administration of antibodies. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. An ordinarily skilled artisan would have had a reasonable expectation of success using the rHuPH20 concentrations taught by Locke as both US’791 and Locke teach the inclusion of rHuPH20 in antibody formulations for subcutaneous administration. It would have further been obvious to use the teachings of US’791, WO’612, Bittner, and Locke as a starting point for routine optimization in order to identify the optimal dose, infusion volume, and flow rate for subcutaneous administration of crenezumab and the concentration of rHuPH20 for the treatment of Alzheimer’s disease. MPEP 2144.05 (II) A. states "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. In this case, US’791 teaches dosage ranges that encompass those of the instant claim and also teaches that the appropriate dosage of antibody will depend on the severity and course of disease, previous therapy, the patient’s clinical history and response to the antibody, and the discretion of the attending physician (page 21, [0212]). US’791 also demonstrates that serum concentration of crenezumab is a function of the dose, demonstrating that the dose of antibody was considered to be a result effective variable. Bittner demonstrates that infusion volumes and infusion rates encompassing those of the instant claim were also known in the art for subcutaneous administration and suggests that the treatment can be according to the individual patient’s comfort level and the addition of additional therapeutics, such as rHuPH20. One of ordinary skill in the art would also reasonably recognize that the infusion volume and time is a result effective variable that will depend on the dose that is given and concentration of the antibody in the composition administered. In this regard it is noted that, as discussed above, WO’612 demonstrates high concentration compositions of anti-Aβ antibodies which, when given at the dosages taught by US’791, encompass the volumes taught by Bittner as possible for subcutaneous infusion. Locke provides concentrations that were known to be effective for the use of rHuPH20 in facilitating subcutaneous administration of therapeutics, including antibodies, and demonstrates that 2000 U/ml has been used in antibody formulations. Locke also demonstrates that, even at much lower concentrations, rHuPH20 is still effective. Locke also teaches that the dose, rate of injection, and type of solution can be adjusted based on an individual basis and can be dependent on age, weight, clinical condition, and laboratory parameters (page 100, right column, paragraph 1), demonstrating that the concentration of rHuPH20 was considered to be a result effective variable that could be modulated for optimal outcomes. Therefore, one of ordinary skill in the art could use the teachings of US’791, WO’612, Bittner, and Locke as a starting point for routine optimization to arrive at the instantly claimed regimen. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00. 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, Joanne Hama can be reached on 571-272-2911. 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. /AUDREY L BUTTICE/Examiner, Art Unit 1647 /SCARLETT Y GOON/Supervisory Patent Examiner Art Unit 1693 Application/Control Number: 18/417,787 Page 2 Art Unit: 1647 Application/Control Number: 18/417,787 Page 3 Art Unit: 1647 Application/Control Number: 18/417,787 Page 4 Art Unit: 1647 Application/Control Number: 18/417,787 Page 5 Art Unit: 1647 Application/Control Number: 18/417,787 Page 6 Art Unit: 1647 Application/Control Number: 18/417,787 Page 7 Art Unit: 1647 Application/Control Number: 18/417,787 Page 8 Art Unit: 1647 Application/Control Number: 18/417,787 Page 9 Art Unit: 1647 Application/Control Number: 18/417,787 Page 10 Art Unit: 1647 Application/Control Number: 18/417,787 Page 11 Art Unit: 1647 Application/Control Number: 18/417,787 Page 12 Art Unit: 1647 Application/Control Number: 18/417,787 Page 13 Art Unit: 1647 Application/Control Number: 18/417,787 Page 14 Art Unit: 1647 Application/Control Number: 18/417,787 Page 15 Art Unit: 1647 Application/Control Number: 18/417,787 Page 16 Art Unit: 1647 Application/Control Number: 18/417,787 Page 17 Art Unit: 1647 Application/Control Number: 18/417,787 Page 18 Art Unit: 1647 Application/Control Number: 18/417,787 Page 19 Art Unit: 1647 Application/Control Number: 18/417,787 Page 20 Art Unit: 1647 Application/Control Number: 18/417,787 Page 21 Art Unit: 1647 Application/Control Number: 18/417,787 Page 22 Art Unit: 1647 Application/Control Number: 18/417,787 Page 23 Art Unit: 1647 Application/Control Number: 18/417,787 Page 24 Art Unit: 1647
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