DETAILED ACTION
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 .
Status of Claims
Claims 50-91 are pending
Claims 50-91 are new.
Claims 50-91 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of prior-filed applications, including US Provisional Application63/220,434 (filed 07/09/2021) under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code:
Pg 25 paragraph [65], http://www.gaain.org/centiloid-project; and
Pg 31 paragraph [090], https://www.eisai.com/news/2019/news201990.html
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 50, 62, 65, and 91 are objected to because of the following informalities:
Claim 50 appears to contain a typographical error in line 1. The phrase “in a subject in a subject having” should be amended to “in a subject having”.
Claims 62 and 65 recite the phrase “amyloid-positive” and claim 65 also recites the phrase “amyloid-negative”. For consistency, it is suggested that these phrases be amended to recite “amyloid positive” and “amyloid negative” without the hyphen between the two words as have been recited in claims 50 and 52, for example.
Claim 91 appears to contain a typographical error. There is an unnecessary space in the phrase “anti- Aβ protofibril antibody” between “anti-“ and “Aβ” which should be deleted.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 50-53 and 57-91 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 50 recites “an Aβ42/40 ratio that indicates amyloid positive status”. The metes and bounds of the claim is unclear because it is not clear what blood sample Aβ42/40 ratio is indicative of amyloid positive status, as the specification does not distinctly define which ratios are, or are not, indicative of amyloid positive status. While the specification discloses exemplary possible rations indicative of amyloid positive status (see paragraph [76] at page 28), those ratios are not defined by the claim and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. This rejection can be obviated by distinctly defining the ratios indicative of amyloid positive status. Claims 51-53 and 57-90 which are dependent claims of claim 50, and which do not provide further limitations on the ratio indicative of amyloid positive status are also rejected here. In addition, the phrase “an Aβ42/40 ratio that indicates amyloid positive status” is also recited in claim 51 in part “d.”.
Claim 52 recites “an Aβ42/40 ratio that indicates amyloid negative status” , as the specification does not distinctly define which ratios are, or are not, indicative of amyloid negative status. While the specification discloses exemplary possible rations indicative of amyloid negative status (see paragraph [76] at page 28), those ratios are not defined by the claim and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. This rejection can be obviated by distinctly defining the ratios indicative of amyloid negative status Claims 53, 65 and 66 which are dependent claims of claim 52, and which do not provide further limitations on the ratio indicative of amyloid negative status are also rejected here. In addition, the phrase “an Aβ42/40 ratio that indicates amyloid negative status” is also recited in claim 53. Further, claim 76 recites the phrase “a further Aβ42/40 ratio obtained after treatment indicates amyloid negative status” which is also unclear regarding the “amyloid negative status” for the same reason.
Claim 61 recites the phrase “…the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or….”. There is insufficient antecedent basis for “the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia” in the claim.
Claim 63 recites the phrase “…the ApoE4 gene”. There is insufficient antecedent basis for “the ApoE4 gene” in the claim.
Claim 73 recites the phrase “…the frequency of administration….”. There is insufficient antecedent basis for “the frequency of administration” in the claim.
Claim 74 recites the phrase “…the dosage of the anti-Aβ protofibril antibody….”. There is insufficient antecedent basis for “the dosage of the anti-Aβ protofibril antibody” in the claim. To be clear, claim 50 recites “a therapeutically effective dose of anti-amyloid β (Aβ) protofibril antibody” but not “a dosage of anti-amyloid β (Aβ) protofibril antibody”. The terms dose and dosage are not strictly synonyms. It is generally understood that the word “dose” means “the specific quantity of a drug given at one time” while the word “dosage” means “the total regimen or schedule of treatment”.
Claim 82 recites the phrase “…the patient….”. There is insufficient antecedent basis for “the patient” in the claim. This rejection can be obviated by amending the claim to recite “the subject”.
Claim 88 recites the phrase “…the use….”. There is insufficient antecedent basis for “the use” in the claim. This rejection can be obviated by amending the claim to recite “the administering”.
Claim 91 recites “an Aβ42/40 ratio that indicates amyloid negative status”. The metes and bounds of the claim is unclear because it is not stated what blood sample Aβ42/40 ratio is indicative of amyloid negative status. This rejection can be obviated by reciting the actual number that is indicative of a amyloid positive status.
Claim Rejections - 35 USC § 103 (first)
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.
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.
Claims 50-58, 61-74, 79, 86 and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Satlin et al. (US20190276560A1 Date Published 2019-09-12) in view of Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659).
The pending claims are drawn to methods of treating Alzheimer’s disease (AD) comprising administering a known AD therapeutic (anti-Aβ protofibril antibody such as BAN2401) to subjects exhibiting a known biomarker (decreased Aβ42/Aβ40 ratio) indicative of the presence of amyloid plaques associated with AD.
Satlin et al. teaches methods and combination therapies for treating, preventing, and/or delaying the onset and/or development of Alzheimer's disease comprising administering a therapeutically effective amount of an anti-Aβ protofibril antibody such as BAN2401 (Abstract and paragraph [0004]). They teach that the anti-Aβ protofibril antibody BAN2401 is a humanized IgG1 monoclonal version of mAb158, wherein mAb158 is a murine monoclonal antibody that was raised to target protofibrils (paragraph [0010]). They also teach that BAN2401 comprises (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:1 and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO:2 (paragraph [0011]). They further teach SEQ ID NOs 5 and 6, stating that SEQ ID NO:5 is the full length sequence of BAN2401 (paragraph [0011]).
The alignment of SEQ ID NO: 1 of Satlin et al. with instant SEQ ID NO: 7 show that these are 100% identical and have the same length of 124 amino acid residues. In addition, the alignment of SEQ ID NO: 2 of Satlin et al. with instant SEQ ID NO: 8 show that these are also 100% identical and are identical in length at 112 amino acid residues (alignment not shown). Further, the alignment of SEQ ID NO: 5 of Satlin et al. with instant SEQ ID NO: 9 show that these are 100% identical in amino acid sequences and are identical in length (454 aa); while the alignment of SEQ ID NO: 6 of Satlin et al. with instant SEQ ID NO: 10 also show that these are 100% identical in amino acid sequences and are identical in length (219 aa).
Of note, instant specification on Pg 33-34 discloses that one of the anti-Aβ protofibril antibody used is BAN2401, also known as lecanemab, and refers to a humanized IgG1 monoclonal version of mAb158, which is a murine monoclonal antibody raised to target protofibrils (paragraph [97]). In addition, instant specification discloses that BAN2401 comprises (i) a heavy chain variable region comprising the amino acid sequence of instant SEQ ID NO: 7 and (ii) a light chain variable region comprising the amino acid sequence of instant SEQ ID NO: 8 and the full length sequences of heavy chain and light chain of BAN2401 are set forth in instant SEQ ID NOs: 9 and 10 (paragraph [97]). Therefore, it is confirmed that the anti-Aβ protofibril antibody of BAN2401 is the same antibody recited in the instant claims.
Satlin et al. teaches in Example 4 “A Placebo-Controlled, Double-Blind, Double-Dummy, Factorial Design, 24 Month Study to Evaluate Safety and Efficacy of Compound X, BAN2401 and the Combination of Compound X and BAN2401 in Subjects with Early Alzheimer's Disease” (paragraphs [077] to [0110]). They teach under the “Inclusion Criteria” that subjects have been diagnosed with mild cognitive Impairment due to Alzheimer's disease—intermediate likelihood if they: 1. Meet the National Institute of Aging—Alzheimer's Association (NIA-AA) core clinical criteria for mild cognitive impairment due to Alzheimer's disease—intermediate likelihood; 2. Have a Clinical Dementia Rating (CDR) score of 0.5 and CDR Memory Box score of 0.5 or greater at Screening and Baseline; and 3. Report a history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening (paragraphs [0085] to [0087]). They also teach that all subjects must have positive biomarker for brain amyloid pathology as indicated by at least one of the following: a) PET assessment of imaging agent uptake into brain; or b) CSF assessment of Aβ(1-42) (paragraph [0094]). They further teach that subjects are randomized according to ApoE genotype, concurrent Alzheimer's disease medication use, and severity of Alzheimer's disease at the time of randomization (paragraph [0084]) and that the subject is an individual having at least one mutated or abnormal gene associated with Alzheimer's disease for example an ApoE4 allele (paragraph [0018]).
Satlin et al. teaches that BAN2401 is administered in normal saline as IV infusion that can be at a dose of 10 mg/kg/biweekly or 10 mg/kg/month (paragraphs [0104] and [0105]). They teach that the dosage of BAN2401 may be dependent upon a number of factors including the frequency of treatment and the nature of the effect desired (paragraph [0040]). They also teach that the efficacy of the treatment, for example in improving cognition and/or reversing cognitive decline, can be assessed by ADAS-Cog14 (paragraphs [0023] and [0109]).
Satlin et al. does not specifically teach a method of treating AD in a subject having, suspected of having, or at risk for developing Alzheimer's disease (AD), comprising: measuring a concentration of amyloid β 1-42 (Aβ42) and a concentration of amyloid β 1-40 (Aβ40) in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40(Aβ42/40 ratio); or the method further comprising, after administering the treatment: measuring a second concentration of Ap42 and a second concentration of Ap40 in a blood sample obtained from the subject to determine a second Ap42/Ap40 ratio; and administering a second treatment comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Ap42/40 ratio that indicates amyloid positive status; or the method further comprising, after administering the treatment: measuring a second concentration of Aβ42 and a second concentration of Ap40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and administering a second treatment comprising a maintenance dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status.
Satlin et al. also does not specifically teach a method of instant claim 50, further comprising, after administering the treatment: measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and administering a second treatment comprising a maintenance dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status; or wherein the Aβ42/40 ratio that indicates amyloid positive status is at most 0.1; or wherein the Aβ42/40 ratio that indicates amyloid positive status is a ratio below about 0.092 to 0.094 or is a ratio below 0.092;
They also do not specifically teach the method of instant claim 50, wherein the concentrations of Aβ42 and Aβ40 used to obtain the Aβ42/40 ratio are measured using an LC MS/MS assay; or wherein the subject has intermediate brain amyloid as measured by PET SUVr prior to treatment with anti-Aβ protofibril antibody; or wherein the treatment is discontinued if, after treatment with the therapeutically effective dose of the anti-protofibril antibody, further measurements of Aβ42 and Aβ40 concentration in a blood sample obtained from the subject result in an Aβ42/Aβ40 ratio that does not indicate a conversion to amyloid negative status; or wherein the treatment comprises a subcutaneous administration of a therapeutically effective dose of the anti-Aβ protofibril antibody; or wherein the frequency of administration is reduced after 18 months or 24 months of treatment; or wherein the dosage of the anti-Aβ protofibril antibody is reduced after 18 months or 24 months of treatment; or wherein the use does not require a titration step prior to administering to the subject a first therapeutically effective dose of the anti-Aβ protofibril antibody.
They do not specifically teach the method of instant claim 52, comprising administering further maintenance doses of the anti-Aβ protofibril antibody to the subject according to a maintenance dosing regimen, wherein the subject has an Aβ42/40 ratio that indicates amyloid negative status; or wherein the Aβ42/40 ratio after treatment with the anti- protofibril antibody is above 0.092; or wherein an elevated Aβ42/40 ratio after treatment with the anti-protofibril antibody indicates that the treatment has converted the subject from amyloid- positive to amyloid-negative status; or wherein the Aβ42/40 ratio after treatment with the anti- protofibril antibody is above 0.092; or
They also do not specifically teach the method of instant claim 70, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody is 720 mg; or wherein the therapeutically effective dose is administered weekly; or wherein the subject is switched to a maintenance dosing regimen comprising administration of a maintenance dose of the anti-Aβ protofibril antibody that is 50% of the subcutaneous administration of the anti-Aβ protofibril antibody.
They further do not specifically teach a method of treating Alzheimer's disease (AD) in a subject, comprising: a) measuring a concentration of amyloid β 1-42 (Aβ42) and a concentration of amyloid p 1-40 (Aβ40) in a blood sample obtained from a subject previously administered an anti-amyloid β (Aβ) protofibril antibody to determine a ratio of Aβ42 to Aβ40 (Aβ42/40 ratio); and b) administering a maintenance dosing regimen comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status.
However, these deficiencies are made up in the teachings of Schindler et al.
Schindler et al. teaches that high-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis (Title). They teach that method of using liquid chromatograph-mass spectrometry assay to measure Aβ42 and Aβ40 in plasma samples of mostly cognitively normal individuals that also performed an amyloid PET scan within 18 months (Abstract Methods). They also teach that plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status which could accurately diagnose brain amyloidosis and thus be used to screen cognitively normal individuals for brain amyloidosis (Abstract Results, Abstract Conclusions and Figures 1A, 1C and 1E). They further teach that the study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal participants (Abstract Classification of evidence).
Schindler et al. teaches that individuals with a positive amyloid PET at baseline had a significantly lower baseline plasma Aβ42/Aβ40 compared to individuals with a negative amyloid PET at baseline (0.115 ± 0.006 vs 0.128 ± 0.009; Figure 1A) and that a plasma Aβ42/Aβ40 cutoff of <0.1218 was considered positive for amyloid status (Pg e1650, column right, second full paragraph). They also teach the utility of plasma Aβ42/Aβ40 as a screening test by stating that screening individuals with a positive plasma Aβ42/Aβ40 first could save or reduce the percentage of amyloid PET scans required as confirmatory for brain amyloid positive status (Pg e1654, column right, first full paragraph). They further teach that amyloid PET was used as the primary reference standard for amyloidosis because it is a well-established biomarker for assessment of brain amyloid burden and that AV45 PET imaging was performed and converted to standardized uptake value ratios (SUVRs) (Pg e1649, column right, second full paragraph).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating Alzheimer’s disease (AD) in just any subject having AD (including a subject that has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate likelihood as taught by Satlin et al.; including a subject that has at least one copy of the ApoE4 gene as taught by Satlin et al.; including a subject that has intermediate brain amyloid as measured by PET SUVr as taught by Schindler, prior to treatment with the anti-Aβ protofibril antibody taught by Satlin et al.), comprising a. measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42/40 as taught by Schindler et al. and b. administering a treatment comprising therapeutically effective dosages of Satlin et al. comprising an anti-amyloid β (Aβ) protofibril antibody to the subject when the subject has an Aβ42/40 ratio that indicates amyloid positive status as taught by Schindler et al. (including a ratio of Aβ42/40 below 0.1 or 0.092 – as Schindler et al. teaches ratios of positive amyloid status are below those of negative amyloid status and that positive patients have an average ratio of 0.109), wherein the anti-Aβ protofibril antibody is anti-Aβ protofibril antibody taught by Satlin et al., because Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis to identify subjects as candidates that would benefit from the administration of AD treatment with a reasonable predictability of success, and because Satlin et al. teaches administrating a therapeutically effective amount of anti-Aβ protofibril antibody BAN2401 as a method for treating AD and Satlin et al. teaches that pathological changes associated with AD include increased formation of amyloid plaques (amyloidosis), amount of soluble Aβ peptide circulating in biological fluids and accumulation of Aβ peptide in the brain (Paragraph [0022]).
Regarding instant claim 51, it would have been obvious to perform the above combined method of Satlin et al. and Schindler et al., that further comprises after administering the treatment: c. measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d. administering a second treatment comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status, because determining a second Aβ42/Aβ40 ratio would identify whether the subject is amyloid positive, which would require further administration of a second treatment of a therapeutically effect dose of anti-Aβ protofibril antibody for effective and optimized management of disease when amyloid status remains positive. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation.
Regarding instant claims 52 and 53, it would have been obvious to perform the above combined method of Satlin et al. and Schindler et al., that further comprises after administering the treatment: c. measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d. administering a second treatment comprising a maintenance dose, and/or further maintenance doses, of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status, because determining a second Aβ42/Aβ40 ratio would identify the amyloid status of the subject and if the subject is amyloid negative, then a change in dose that to one that is a maintenance dose of anti-Aβ protofibril antibody can be made for effective and optimized management of disease that has exhibited successful responsiveness to the anti-Aβ protofibril antibody when the amyloid status is no longer positive. One of skill in the art would recognize maintenance doses or maintenance dosing regimens usually comprise of lower dose and longer dosing intervals which has the advantage of reducing cost. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claims 62 and 64, it would have been obvious to perform the above combined method of Satlin et al. and Schindler et al., wherein the amyloid-positive status is confirmed by a PET assessment as taught by Schindler et al., or wherein the concentrations of Aβ42 and Aβ40 used to obtain the Aβ42/40 ratio are measured using an LC MS/MS assay also as taught by Schindler et al. because PET assessment is a well-established technique used for determining levels of brain amyloid and because LC MS/MS assay is a routine technique in determining levels of biomarkers in bodily fluids obtained from subjects.
Regarding instant claim 66, while cited references do not demonstrate the combined method wherein a Aβ42/Aβ40 ratio after treatment is above 0.092, a Aβ42/Aβ40 ratio after treatment would be expected in subjects therapeutically treated by the combined method because Schindler et al. teaches individuals with a negative amyloid PET have a Aβ42/Aβ40 ratio 0.128 ± 0.009 – above that of those with a positive amyloid PET.
Regarding instant claim 67, it would be obvious to perform the above combined method of Satlin et al. and Schindler et al., wherein the anti-protofibril antibody treatment is discontinued if measurements of blood Aβ42/Aβ40 ratio, upon treatment with a therapeutically effective dose of anti-protofibril antibody, does not indicate conversion to amyloid negative status so that the anti-Aβ protofibril antibody can be switched to another treatment to better manage AD in the subject.
Regarding instant claims 68 and 69, it would be obvious to perform the above combined method of Satlin et al. and Schindler et al., wherein the treatment comprises an intravenous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject as taught by Satlin et al.; or wherein the therapeutically effective dose is administered every 2 weeks as taught by Satlin et al. because Satlin et al. has administered these doses and dosing regimen for a method for treating AD.
Regarding instant claim 70, it would be obvious to perform the above combined method of Satlin et al. and Schindler et al., wherein the treatment comprises a subcutaneous administration of a therapeutically effective dose of the anti-Aβ protofibril antibody, because it would be obvious to try a different administration route to the intravenous infusion route taught by Satlin et al. since advantages of a subcutaneous injection over an intravenous (IV) route include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, regarding instant claim 71, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is 720 mg, it would be obvious to try different doses when given subcutaneously in order to optimize the treatment. Further, regarding instant claim 72, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is administered weekly, it would be obvious to try different dosing intervals given subcutaneously in order to optimize the treatment. Even further, regarding instant claim 79, it would be obvious to have the subject switched to a maintenance dosing regimen comprising administration of a maintenance dose of the anti-Aβ protofibril antibody that is 50% of the subcutaneous administration of the anti-Aβ protofibril antibody, because once the subject is amyloid negative which indicates that the subject has been responsive, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 73, it would be obvious to perform the above combined method of Satlin et al. and Schindler et al., wherein the frequency of administration is reduced after 18 months or 24 months of treatment because the treatment frequency can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in frequence of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 74, it would be obvious to perform the above combined method of Satlin et al. and Schindler et al., wherein the dosage of the anti-Aβ protofibril antibody is reduced after 18 months or 24 months of treatment because the dosage can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in dosage of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 86, it would be obvious to perform the above combined method of Satlin et al. and Schindler et al., and expect that the treatment delays clinical decline as measured by an ADAS-Cog as taught by Satlin et al.
Regarding instant claim 88, it would be obvious to perform the above combined method of Satlin et al. and Schindler et al., and optimize the dosing regimen such that the method does not require a titration step prior to administering to the subject a first therapeutically effective dose of the anti-Aβ protofibril antibody because this could improve patient convenience and speed up the time to reach a full therapeutic effect.
This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (second)
Claims 50-58, 59, 60, 61-74, 79, 86 and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Satlin et al. (US20190276560A1 Date Published 2019-09-12) and Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659) as applied to claims 50-58, 61-74, 79, 86 and 88-91 above and in further view of Aisen et al. (J Prev Alzheimer’s Dis 8, 306–312; 2021; Available online 24 May 2021).
The combined teachings of Satlin et al. and Schindler et al. render obvious instant claims 50-58, 61-74, 79, 86 and 88-91 as discussed above in the first 103 rejection.
Satlin et al. and Schindler et al. do not specifically teach said combined method wherein the subject has pre-Alzheimer’s disease (pre-AD); or that the subject is cognitively normal but exhibits at least one biomarker of AD.
However, these deficiencies are made up in the teachings of Aisen et al.
Aisen et al. teaches that anti-Aβ monoclonal antibody lecanemab (BAN 2401) was used in the AHEAD Study comprising two Phase 3 secondary prevention trials, namely the A45 trial and the A3 trial trials, but at different dosing regimen depending on baseline amyloid burden (Pg 308, column right, third full paragraph, lines 1-6). They teach that treatment was evaluated across the continuum of early-to-late preclinical AD as determined by PET assessment which enabled the visualization of amyloid plaques and tau neurofibrillary tangles (Pg 308, column right, third full paragraph, lines 6-11). They further teach that the A3 trial aimed to capture people with a measurable amyloid PET signal that is below a conventional threshold of amyloidosis, or “intermediate” levels of amyloid that correlate with early preclinical or “pre-preclinical” AD (Pg 308, column right, fourth paragraph spanning Pg 309 column left).
Aisen et al. teaches the DIAN-TU platform which is a 4-year secondary prevention trial in participants with DIAD mutations and expected onset ranging from −15 to +10 years and Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild cognitive impairment), or 1 (mild cognitive impairment consistent with early dementia) (Pg 308, column left, first full paragraph lines 1-7). They teach that DIAN enrolled participants from around the world with dominantly inherited AD (DIAD) mutations that confer nearly 100 percent certainty of developing AD and established the progression of biomarkers across the continuum of the disease and demonstrated a biomarker profile associated with presymptomatic disease which provided a rationale for starting a prevention trial in the presymptomatic stage (Pg 307, column left, second full paragraph lines 6-14 and Figure 1). They also teach that the nearly 200 participants were enrolled and randomized to receive Eli Lilly's solanezumab (a soluble anti-amyloid-beta monoclonal antibody), Roche's gantenerumab (an aggregated anti-amyloid monoclonal antibody), or placebo (Pg 308, column left, first full paragraph lines 7-11).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating Alzheimer’s disease (AD) in a subject having AD as taught by the combined method of Satlin et al. (anti-Aβ monoclonal antibody BAN2401) and Schindler et al. (measuring plasma Aβ42/40 ratio) described in the first 103 rejection above, and wherein the subject is cognitively normal, happens to have a biomarker of AD, and has preclinical Alzheimer’s disease as taught by Aisen et al., because Aisen et al. teaches that people with preclinical AD could benefit from treatment with the anti-Aβ monoclonal antibody BAN 2401 as studied in the AHEAD A3 and A45 trials.
These are examples of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (third)
Claims 50-58, 61-74, 75, 76, 77, 78, 79, 82, 83, 86 and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Satlin et al. (US20190276560A1 Date Published 2019-09-12) and Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659) as applied to claims 50-58, 61-74, 79, 86 and 88-91 above and in further view of NCT03887455 (Record History 2020-03-12).
The combined teachings of Satlin et al. and Schindler et al. render obvious instant claims 50-58, 61-74, 79, 86 and 88-91 as discussed above in the first 103 rejection.
Satlin et al. and Schindler et al. do not specifically teach said combined method wherein the subject is switched to a maintenance dosing regimen after 18 months or 24 months of treatment; or wherein said maintenance dosing regimen comprises an intravenous infusion of the anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to weight of the subject, administered monthly; or wherein said maintenance dose is administered at a dose and/or frequency selected to maintain an Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status.
They also do not specifically teach said combined method wherein the subject is sequentially or simultaneously administered at least one additional AD medication.
However, these deficiencies are made up in the teachings of NCT03887455.
NCT03887455 teaches the study that evaluated the efficacy of BAN2401 in participants with early Alzheimer's disease (EAD) by determining the superiority of BAN2401 compared with placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months of treatment in the Core Study (Brief Summary). They teach that BAN2401 is administered at a dose of 10 mg/kg biweekly as an i.v. infusion in the Core Study (Arms and Interventions). They also teach that an Extension Phase of the study evaluated whether long-term effects of BAN2401 is maintained over time where BAN2401 is administered at a dose of 10 mg/kg biweekly as an i.v. infusion after the Core Study (Brief Summary and Arms and Interventions). They further teach that participants can be receiving an approved Alzheimer's disease treatment such as acetylcholinesterase inhibitor (AChEIs) or memantine or both for Alzheimer's disease (Criteria; Key Inclusion Criteria that must be met by all participants).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating Alzheimer’s disease (AD) in a subject having AD as taught by the combined method of Satlin et al. (anti-Aβ monoclonal antibody BAN2401) and Schindler et al. (measuring plasma Aβ42/40 ratio) described in the first 103 rejection above, and wherein after 18 months of treatment of BAN2401 as taught by NCT03887455, the subject is switched to a maintenance dosing also as taught by NCT03887455 in the Extension Phase. This is because of the potential advantage that BAN2401 could provide in terms of maintained long term beneficial effects in treated subjects as taught by NCT03887455. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Regarding instant claims 76 and 82, it would be obvious to perform the above combined method, wherein the subject is switched to a maintenance dosing regimen that maintains an Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status when a further Aβ42/40 ratio obtained after treatment indicates amyloid negative status because when the subject has shown responsiveness to the treatment dose based on the blood Aβ42/40 ratio a maintenance dosing regimen corresponds to an effort to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of a responsive subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 77, it would have been obvious to optimize the combined method wherein the maintenance dosing regimen comprises i.v. infusion of BAN2401 at a dose of 10 mg/kg administered monthly because NCT03887455 teaches a dose of 10 mg/kg administered biweekly in the Extension Phase and because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the value or parameter of the “monthly administration” in the instant claim is obvious.
Regarding instant claim 78, it would have been obvious to perform the combined method and optimize the maintenance dosing regimen to comprise subcutaneous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 360 mg, administered weekly, because of the advantages of using subcutaneous injection over an intravenous (IV) route include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, the dose of 360 mg and the frequency of weekly administration is obvious because these would be routine optimization of a dose based on route of administration and based on the responsiveness of the subject.
Further, regarding instant claim 83, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455 because the additional medications have different mechanisms of action that can target the various biological manifestations of Alzheimer’s disease such that a multi-drug or multi-action approach can better protect brain function.
This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (fourth)
Claims 50-58, 61-79, 80, 81, 82, 83, 86 and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Satlin et al. (US20190276560A1 Date Published 2019-09-12), Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659) and NCT03887455 (Record History 2020-03-12) as applied to claims 50-58, 61-79, 82, 83, 86 and 88-91 above and in further view of Rodriguez et al. (Acta Neuropathol. 2020 Sep;140(3):267-278).
The combined teachings of Satlin et al., Schindler et al. and NCT03887455 render obvious instant claims 50-58, 61-79, 82, 83, 86 and 88-91 as discussed above in the third 103 rejection.
Satlin et al., Schindler et al. and NCT03887455 do not specifically teach comprising detecting, before switching to a maintenance dose, a decrease in p-tau181 in a blood sample from the subject.
However, these deficiencies are made up in the teachings of Rodriguez et al.
Rodriguez et al. teaches that one of the core AD CSF biomarkers is phosphorylated tau181 (p-tau181) which reflects tau pathology in AD (Introduction). They teach that blood p-tau181 has shown promising results that prove it to be a reliable tool for AD diagnosis and correlates well with in vivo assessments of Aβ and tau pathologies (Introduction). They also teach that plasma p-tau181 accurately predicts Alzheimer’s disease neuropathology where they found patients in the AD pathology group had significantly higher plasma p-tau181 as compared to the control and non-AD pathology groups (Title, Abstract and Figures 2, 3 and 4). They further teach that plasma p-tau181 may be used routinely to improve the confidence in administering symptomatic treatment or better inform on patient management, aiding in the clinical management of the disease (Abstract and Pg 275, column left, second full paragraph, lines 26-29). They even further teach that plasma p-tau181 may be used in both clinical practice and clinical trials as a first screening tool that may be followed, if needed, by CSF or PET biomarker confirmation (Pg 275, column left, second full paragraph, line 29 to end of paragraph in column right lines 1-2).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating Alzheimer’s disease (AD) in a subject having AD as taught by the combined method of Satlin et al. (anti-Aβ monoclonal antibody BAN2401), Schindler et al. (measuring plasma Aβ42/40 ratio) and NCT03887455 (after 18 months of treatment of BAN2401 the subject is switched to a maintenance dosing) as described in the third 103 rejection above, and combine it with detecting the levels of plasma p-tau181 from the subject as taught by Rodriguez et al. and optimize the timing of said detection to before switching to a maintenance dose to detect for a decrease in p-tau181 because Rodriguez et al. teaches that plasma p-tau181 is significantly higher in AD patients which translates to mean that a decrease in p-tau181 after antibody treatment indicates a response to the treatment and an improvement of the disease. In addition, Rodriguez et al. teaches that using plasma p-tau181 as a biomarker to track disease progression and therapeutic response could have an advantage because plasma detection is more cost efficient compared to CSF testing and PET scan that are much more resource-intensive and more costly.
Claim Rejections - 35 USC § 103 (fifth)
Claims 50-58, 61-79, 82, 83, 84, 86 and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Satlin et al. (US20190276560A1 Date Published 2019-09-12), Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659) and NCT03887455 (Record History 2020-03-12) as applied to claims 50-58, 61-79, 82, 83, 86 and 88-91 above and in further view of Roberts et al. (Alzheimer's & Dementia, 15: P1598-P1598; First published: 01 July 2019; AAIC Wednesday Poster Abstracts).
The combined teachings of Satlin et al., Schindler et al. and NCT03887455 render obvious instant claims 50-58, 61-79, 82, 83, 86 and 88-91 as discussed above in the third 103 rejection.
Satlin et al., Schindler et al. and NCT03887455 do not specifically teach said combined method wherein the additional AD medication is E2814.
However, these deficiencies are made up in the teachings of Roberts et al
Roberts et al. teaches that E2814 is a novel humanised IgG1, high affinity antibody that is bi-epitopic for 4R tau isoforms (Background and Results). They teach that E2814 inhibited tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds (Results). They also teach that in AD brain, E2814 was shown to bind both different types of isolated tau filaments and pathological tau structures in tissue sections and thus the data suggest that E2814 should be investigated further in human clinical trials (Results and Conclusions).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating Alzheimer’s disease (AD) in a subject having AD as taught by the combined method of Satlin et al. (anti-Aβ monoclonal antibody BAN2401), Schindler et al. (measuring plasma Aβ42/40 ratio) and NCT03887455 (subject is simultaneously administered at least one additional AD medication) as described in the third 103 rejection above, and wherein the additional AD medication is E2814 as taught by Roberts et al. because E2814 has the advantage of targeting a different pathological manifestation of Alzheimer’s disease which is the biomarker tau and because it can inhibit tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds, making the combination of anti-Aβ monoclonal antibody BAN2401 and anti-tau antibody E2814 a superior therapy for AD.
Claim Rejections - 35 USC § 103 (sixth)
Claims 50-58, 61-74, 79, 85, 86 and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Satlin et al. (US20190276560A1 Date Published 2019-09-12) and Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659) as applied to claims 50-58, 61-74, 79, 86 and 88-91 above and in further view of Swanson et al. (Alzheimer's & Dementia, 14: P1668-P1668; First published: 01 July 2018).
The combined teachings of Satlin et al. and Schindler et al. render obvious instant claims 50-58, 61-74, 79, 86 and 88-91 as discussed above in the first 103 rejection.
Satlin et al. and Schindler et al. do not specifically teach said combined method wherein the method results in a reduction or a slowing of increase the tau cerebrospinal fluid biomarker.
However, these deficiencies are made up in the teachings of Swanson et al.
Swanson et al. teaches that BAN2401 produced dose-dependent effects on amyloid PET, clinical endpoints, and tau CSF biomarkers (Results lines 1-2). They teach that BAN2401 produced statistically significant reduction in brain amyloid across all doses tested with the top dose of 10 mg/kg bi-weekly achieving an adjusted mean change from baseline versus placebo at 12 months and at 18 months (Results lines 3-6).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating Alzheimer’s disease (AD) in a subject having AD as taught by the combined method of Satlin et al. (anti-Aβ monoclonal antibody BAN2401) and Schindler et al. (measuring plasma Aβ42/40 ratio) described in the first 103 rejection above, and wherein the method results in a reduction or a slowing of increase of the tau cerebrospinal fluid biomarker as taught by Swanson et al. because Swanson et al. teaches that BAN2401 showed efficacy in significantly reducing brain amyloid in study patients. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (seventh)
Claims 50-58, 61-74, 79, 86, 87, and 88-91 are rejected under 35 U.S.C. 103 as being unpatentable over Satlin et al. (US20190276560A1 Date Published 2019-09-12) and Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659) as applied to claims 50-58, 61-74, 79, 86 and 88-91 above and in further view of Ferrero et al. (Translational Research & Clinical Interventions, (2016) 2: 169-176).
The combined teachings of Satlin et al. and Schindler et al. render obvious instant claims 50-58, 61-74, 79, 86 and 88-91 as discussed above in the first 103 rejection.
Satlin et al. and Schindler et al. do not specifically teach said combined method further comprising monitoring for ARIA-E and/or ARIA-H by MRI.
However, these deficiencies are made up in the teachings of Ferrero et al.
Ferrero et al. teaches MRI scans (including T1, T2, fluid-attenuated inversion recovery, and gradient echo) taken at screening and at weeks 3, 11, and 24 were evaluated to perform assessments of all MRIs for ARIA-edema/effusion (ARIA-E) and/or ARIA-microhemorrhage/hemosiderosis (ARIA-H) on patients undergoing treatment with aducanumab, a human monoclonal antibody selective for aggregated forms of amyloid beta and investigated as a disease-modifying treatment for Alzheimer's disease (AD) (Abstract Instruction and Pg 170, column right, fourth full paragraph).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating Alzheimer’s disease (AD) in a subject having AD as taught by the combined method of Satlin et al. (anti-Aβ monoclonal antibody BAN2401) and Schindler et al. (measuring plasma Aβ42/40 ratio) described in the first 103 rejection above, and wherein said combined method further comprises monitoring for ARIA-E and/or ARIA-H by MRI as taught by Ferrero et al. because monitoring for ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) or ARIA-H (Amyloid-Related Imaging Abnormalities-Hemosiderin) allows for catching dangerous side effects of treatments early, so that the decision to pause or stop administration of antibody BAN2401 can be made to prevent severe or life-threatening brain damage. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
First NSDP: Application No. 17/250,448
Claims 50-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 44, 48, 50, 180, 181, 182, 183, 184, 185, 187, 188, 189, 199, 208, 210, 213 and 217 of copending Application No. 17/250,448 in view of Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659), Satlin et al. (US20190276560A1 Date Published 2019-09-12), Aisen et al. (J Prev Alzheimer’s Dis 8, 306–312; 2021; Available online 24 May 2021), NCT03887455 (Record History 2020-03-12), Rodriguez et al. (Acta Neuropathol. 2020 Sep;140(3):267-278), Roberts et al. (Alzheimer's & Dementia, 15: P1598-P1598; First published: 01 July 2019; AAIC Wednesday Poster Abstracts), Swanson et al. (Alzheimer's & Dementia, 14: P1668-P1668; First published: 01 July 2018) and Ferrero et al. (Translational Research & Clinical Interventions, (2016) 2: 169-176).
The copending claims are drawn to a method of treating subjects who have early Alzheimer’s disease comprising administering a treatment comprising a therapeutically effective amount of the same anti-Aβ protofibril antibody as the instant claims. However, the copending claims do not specifically also recite the method comprises: a) measuring a concentration of amyloid β 1-42 (Aβ42) and a concentration of amyloid β 1-40 (Aβ40) in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40(Aβ42/40 ratio); and b) administering said treatment to the subject having an Aβ42/40 ratio that indicates amyloid positive status; or administering subsequent treatments; or administering dosing regimens; or monitoring steps; or administering additional AD medication as recited by instant claims.
However, these deficiencies are rendered obvious by Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al. and Swanson et al.
The teachings of Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al., and Swanson et al. are discussed above.
However, it would be obvious to perform a combined method of treating Alzheimer’s disease (AD) of copending claims in view of cited references, in a subject having AD comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42/40 as taught by Schindler et al. wherein the subject has an Aβ42/40 ratio that indicates amyloid positive status also as taught by Schindler et al., and b) administering a treatment comprising a therapeutically effective amount of the anti-Aβ protofibril antibody as taught by the copending claims, because Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis to identify subjects as candidates that would benefit from the administration of AD treatment with a reasonable predictability of success.
Regarding instant claim 51, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status, because determining a second Aβ42/Aβ40 ratio would identify whether the subject remains amyloid positive, which would require further administration of a second treatment of a therapeutically effect dose of anti-Aβ protofibril antibody for effective and optimized management of disease when amyloid status remains positive. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claims 52 and 53, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a maintenance dose, and/or further maintenance doses, of the copending anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status, because determining a second Aβ42/Aβ40 ratio would identify the amyloid status of the subject and if the subject is amyloid negative, then a change in dose that to one that is a maintenance dose of anti-Aβ protofibril antibody can be made for effective and optimized management of disease when the amyloid status is no longer positive. Maintenance doses or maintenance dosing regimens usually comprise of lower dose and longer dosing intervals which has the advantage of reducing cost. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claim 54, it would have been obvious to perform the above combined method, wherein the Aβ42/40 ratio that indicates amyloid positive status is at most 0.1 because those patients with a Aβ42/40 ratio of 0.1 or below would be considered positive since Schindler et al. teaches Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status and that positive patients have an average ratio of 0.109 while negative patients have an average ratio of 0.119. Similarly, instant claims 55 and 56 are obvious because Schindler et al. teaches a ratio of 0.109 and lower for a Aβ42/40 ratio is indicative of positive amyloid status. Further, instant claim 65 is obvious because Schindler et al. teaches that Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status, therefore an elevated Aβ42/40 ratio after treatment with the copending anti-protofibril antibody indicates that the treatment has converted the subject from amyloid-positive to amyloid-negative status.
Regarding instant claim 57, copending claims teaches subjects have Alzheimer’s disease.
Regarding instant claim 58, it would have been obvious to perform the above combined method, wherein the subject has early AD as recited by copending claims, because early treatment has the advantage of stopping brain changes early to protect the brain from progressive disease.
Regarding instant claim 61, it would have been obvious to perform the above combined method, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate likelihood as recited by copending claims because it would be beneficial to treat the disease even when there is only mild cognitive impairment so that progression of disease can be delayed.
Regarding instant claims 62 and 64, it would have been obvious to perform the above combined method, wherein the amyloid-positive status is confirmed by a PET assessment as taught by Schindler et al., or wherein the concentrations of Aβ42 and Aβ40 used to obtain the Aβ42/40 ratio are measured using an LC MS/MS assay also as taught by Schindler et al. because PET assessment is a well-established technique used for determining levels of brain amyloid and because LC MS/MS assay is a routine technique in determining levels of biomarkers in bodily fluids obtained from subjects.
Regarding instant claim 63, it would have been obvious to perform the above combined method, wherein the subjects are ApoE4-positive as recited in copending claims because it is well known in the art that ApoE4 gene variant is a common genetic risk factor for AD and so treatment of said subject would improve symptoms.
Regarding instant claim 66, while copending and cited references do not demonstrate the combined method wherein a Aβ42/Aβ40 ratio after treatment is above 0.092, the combined method appears to be the same as that of instant claim 66 because the combined method administers the same reagents to the same subjects.
Regarding instant claim 67, it would be obvious to perform the above combined method, wherein the copending anti-protofibril antibody treatment is discontinued if measurements of blood Aβ42/Aβ40 ratio, upon treatment with a therapeutically effective dose of anti-protofibril antibody, does not indicate conversion to amyloid negative status so that the anti-Aβ protofibril antibody can be switched to another treatment to better manage AD in the subject.
Regarding instant claim 68, it would be obvious to perform the above combined method, wherein the treatment comprises an intravenous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject because this method is recited by copending claims. Further, regarding instant claim 69, the therapeutically effective dose is administered every 2 weeks would be an optimization of the dosing regimen that is obvious.
Regarding instant claim 70, it would be obvious to perform the above combined method, wherein the treatment comprises a subcutaneous administration of a therapeutically effective dose of the copending anti-Aβ protofibril antibody, because copending claims recite administration via the subcutaneous route and because of the advantages of a subcutaneous injection over an intravenous (IV) route include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, regarding instant claim 71, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is 720 mg, it would be obvious to try different doses when given subcutaneously in order to optimize the treatment. Further, regarding instant claim 72, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is administered weekly, it would be obvious to try different dosing intervals given subcutaneously in order to optimize the treatment. Even further, regarding instant claim 79, it would be obvious to have the subject switched to a maintenance dosing regimen comprising administration of a maintenance dose of the copending anti-Aβ protofibril antibody that is 50% of the subcutaneous administration of the anti-Aβ protofibril antibody, because once the subject is amyloid negative which indicates that the subject has been responsive, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 73, it would be obvious to perform the above combined method, wherein the frequency of administration is reduced after 18 months or 24 months of treatment because the treatment frequency can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in frequence of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 74, it would be obvious to perform the above combined method, wherein the dosage of the anti-Aβ protofibril antibody is reduced after 18 months or 24 months of treatment because the dosage can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in dosage of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 86, it would be obvious to perform the above combined method, and expect that the treatment delays clinical decline as measured by an ADAS-Cog as recited by copending claims and as taught by Satlin et al.
Regarding instant claim 88, it would be obvious to perform the above combined method, and optimize the dosing regimen such that the method does not require a titration step prior to administering to the subject a first therapeutically effective dose of the anti-Aβ protofibril antibody as recited by copending claims because this could improve patient convenience and speed up the time to reach a full therapeutic effect.
Regarding instant claim 89, it would be obvious to perform the above combined method, wherein the subject has intermediate brain amyloid as measured by PET SUVr as taught by Schindler, prior to treatment with the copending anti-Aβ protofibril antibody because PET is an established method for diagnosis of AD base on the determination of brain amyloid status.
Regarding instant claim 90, it would be obvious to perform the above combined method, wherein the anti-Aβ protofibril antibody comprises the amino acid sequence of SEQ ID NOs: 11 and 12 as recited by copending claims as the heavy chain and light chain respectively, because an antibody comprising a variable heavy chain region, a heavy chain constant region, a variable light chain region and a light chain constant region would be an antibody Fab fragment that has the benefits of superior structural stability and a lower tendency to aggregate due to constant domain pairing and disulfide bonds compared to an Fv or scFv fragment.
Further, regarding instant claim 91, it would be obvious to perform the combined method of treating Alzheimer’s disease (AD) in a subject comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40 as taught by Schindler et al. wherein the subject had been administered the copending anti-amyloid β (Aβ) protofibril antibody; and b) administering a maintenance dosing regimen as recited by copending claims comprising a therapeutically effective dose of the copending anti-Aβ protofibril antibody to the subject, wherein the subject has an Aβ42/40 ratio that indicates amyloid negative status as taught by Schindler et al., because (1) Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis which can identify subjects that have amyloid negative status upon prior or previous AD treatment which translates to improved AD condition; (2) Satlin et al. teaches administrating a therapeutically effective amount of anti-Aβ protofibril antibody BAN2401 as a method for treating AD; and (3) a maintenance dosing regimen, usually a lower dose administered at longer intervals, can lower cost of therapy and can offer continued protection of the brain in a safe and stable manner.
Regarding instant claim 59, it would be obvious to perform the above combined method, wherein the subject has preclinical Alzheimer’s disease as taught by Aisen et al., because Aisen et al. teaches that people with preclinical AD could benefit from treatment with the anti-Aβ monoclonal antibody BAN 2401, which is the alternative name for the copending antibody, as studied in the AHEAD A3 and A45 trials.
Regarding instant claim 60, it would be obvious to perform the above combined method, wherein the subject is cognitively normal but exhibits at least one biomarker of AD as taught in the DIAN-TU platform trial by Aisen et al. because there could be an advantage in starting preventative treatment of AD in the presymptomatic stage as taught by Aisen et al.
Regarding instant claim 75, it would be obvious to perform the above combined method, wherein after 18 months of treatment of the copending antibody, the subject is switched to a maintenance therapy as recited by copending claims. This is because a maintenance therapy is usually a lower dose administered at longer intervals, therefore lowering cost of therapy while offering continued protection of the brain in a safe and stable manner.
Regarding instant claim 76, it would be obvious to perform the above combined method, wherein the subject is switched to a maintenance dosing regimen when a further Aβ42/40 ratio obtained after treatment indicates amyloid negative status because when the subject has shown responsiveness to the treatment dose based on the blood Aβ42/40 ratio, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 77, it would have been obvious to optimize the above combined method, wherein the maintenance dosing regimen comprises i.v. infusion of copending antibody at a dose of 10 mg/kg as recited by copending claims, and optimized to be administered monthly because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the value or parameter of the “monthly administration” in the instant claim is obvious.
Regarding instant claim 78, it would have been obvious to perform the above combined method, wherein the maintenance dosing regimen comprises of administration of copending antibody via subcutaneous route as recited by copending claims, and wherein the therapeutically effective dose of 360 mg, administered weekly, is an optimization of the dosing regimen because of the advantages of using subcutaneous injection over an intravenous (IV) route which include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, the dose of 360 mg and the frequency of weekly administration is obvious because these would be routine optimization of a dose based on route of administration and based on the responsiveness of the subject.
Regarding instant claim 82, it would have been obvious to optimize the above combined method, wherein the maintenance dose is optimized and administered at a dose and/or frequency selected to maintain an Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the value or parameter of “the maintenance dose” that results in the intended effect of “maintaining the Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status” in the instant claim is obvious.
Further, regarding instant claim 83, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455 because the additional medications have different mechanisms of action that can target the various biological manifestations of Alzheimer’s disease such that a multi-drug or multi-action approach can better protect brain function.
Regarding instant claim 80, it would have been obvious to perform the above combined method, wherein after 18 months of treatment of copending antibody the subject is switched to a maintenance dosing as recited by copending claims, and combine it with detecting the levels of plasma p-tau181 from the subject as taught by Rodriguez et al. and also optimize the timing of said detection to before switching to a maintenance dose to detect for a decrease in p-tau181 because Rodriguez et al. teaches that plasma p-tau181 is significantly higher in AD patients which translates to mean that a decrease in p-tau181 after antibody treatment indicates a response to the treatment and an improvement of the disease. In addition, Rodriguez et al. teaches that using plasma p-tau181 as a biomarker to track disease progression and therapeutic response could have an advantage because plasma detection is more cost efficient compared to CSF testing and PET scan that are much more resource-intensive and more costly.
Regarding instant claim 84, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455, and wherein the additional AD medication is E2814 as taught by Roberts et al. because E2814 has the advantage of targeting a different pathological manifestation of Alzheimer’s disease which is the biomarker tau and because it can inhibit tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds, making the combination of copending anti-Aβ monoclonal antibody and anti-tau antibody E2814 a superior therapy for AD.
Regarding instant claim 85, it would have been obvious to perform the above combined method, wherein the method results in a reduction or a slowing of increase of the tau cerebrospinal fluid biomarker as taught by Swanson et al. because Swanson et al. teaches that BAN2401, the alternative name for the copending antibody, showed efficacy in significantly reducing brain amyloid in study patients.
Regarding instant claim 87, it would have been obvious to perform the above combined method, wherein said combined method further comprises monitoring for ARIA-E and/or ARIA-H by MRI as recited by copending claims because monitoring for ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) or ARIA-H (Amyloid-Related Imaging Abnormalities-Hemosiderin) allows for catching dangerous side effects of treatments early, so that the decision to pause or stop administration of antibody BAN2401 can be made to prevent severe or life-threatening brain damage as taught by Ferrero et al.
This is a provisional nonstatutory double patenting rejection.
Second NSDP: Application No. 17/857,931
Claims 50-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4- 8 of copending Application No. 17/857,931 in view of Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659), Satlin et al. (US20190276560A1 Date Published 2019-09-12), Aisen et al. (J Prev Alzheimer’s Dis 8, 306–312; 2021; Available online 24 May 2021), NCT03887455 (Record History 2020-03-12), Rodriguez et al. (Acta Neuropathol. 2020 Sep;140(3):267-278), Roberts et al. (Alzheimer's & Dementia, 15: P1598-P1598; First published: 01 July 2019; AAIC Wednesday Poster Abstracts), Swanson et al. (Alzheimer's & Dementia, 14: P1668-P1668; First published: 01 July 2018) and Ferrero et al. (Translational Research & Clinical Interventions, (2016) 2: 169-176).
The copending claims are drawn to a method of treating Alzheimer’s disease comprising administering to a subject in need thereof a therapeutically effective amount of the same anti-Aβ protofibril antibody as the instant claims. However, the copending claims do not specifically also recite the method comprises: a) measuring a concentration of amyloid β 1-42 (Aβ42) and a concentration of amyloid β 1-40 (Aβ40) in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40(Aβ42/40 ratio); and b) administering said anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status; or administering subsequent treatments; or administering dosing regimens; or monitoring steps; or administering additional AD medication as recited by instant claims.
However, these deficiencies are rendered obvious by Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al.
The teachings of Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al. are discussed above.
However, it would be obvious to perform a combined method of treating Alzheimer’s disease (AD) of copending claims in view of cited references, in a subject having AD comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42/40 as taught by Schindler et al. wherein the subject has an Aβ42/40 ratio that indicates amyloid positive status also as taught by Schindler et al., and b) administering a treatment comprising a therapeutically effective amount of the anti-Aβ protofibril antibody as recited by the copending claims, because Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis to identify subjects as candidates that would benefit from the administration of AD treatment with a reasonable predictability of success.
Regarding instant claim 51, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status, because determining a second Aβ42/Aβ40 ratio would identify whether the subject is amyloid positive, which would require further administration of a second treatment of a therapeutically effect dose of anti-Aβ protofibril antibody for effective and optimized management of disease when amyloid status remains positive. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claims 52 and 53, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a maintenance dose, and/or further maintenance doses, of the copending anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status, because determining a second Aβ42/Aβ40 ratio would identify the amyloid status of the subject and if the subject is amyloid negative, then a change in dose to one that is a maintenance dose of anti-Aβ protofibril antibody can be made for effective and optimized management of disease when the amyloid status is no longer positive. Maintenance doses or maintenance dosing regimens usually comprise of lower dose and longer dosing intervals which has the advantage of reducing cost. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claim 54, it would have been obvious to perform the above combined method, wherein the Aβ42/40 ratio that indicates amyloid positive status is at most 0.1 because those patients with a Aβ42/40 ratio of 0.1 or below would be considered positive since Schindler et al. teaches Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status and that positive patients have an average ratio of 0.109 while negative patients have an average ratio of 0.119. Similarly, instant claims 55 and 56 are obvious because Schindler et al. teaches a ratio of 0.109 and lower for a Aβ42/40 ratio is indicative of positive amyloid status. Further, instant claim 65 is obvious because Schindler et al. teaches that Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status, therefore an elevated Aβ42/40 ratio after treatment with the copending anti-protofibril antibody indicates that the treatment has converted the subject from amyloid- positive to amyloid-negative status.
Regarding instant claim 61, it would have been obvious to perform the above combined method, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate likelihood as recited by copending claims taught by Satlin et al. because it would be beneficial to treat the disease even when there is only mild cognitive impairment so that progression of disease can be delayed.
Regarding instant claims 62 and 64, it would have been obvious to perform the above combined method, wherein the amyloid-positive status is confirmed by a PET assessment as taught by Schindler et al., or wherein the concentrations of Aβ42 and Aβ40 used to obtain the Aβ42/40 ratio are measured using an LC MS/MS assay also as taught by Schindler et al. because PET assessment is a well-established technique used for determining levels of brain amyloid and because LC MS/MS assay is a routine technique in determining levels of biomarkers in bodily fluids obtained from subjects.
Regarding instant claim 63, it would have been obvious to perform the above combined method, wherein the subject has at least one copy of the ApoE4 gene as taught by Satlin et al. because it is well known in the art that ApoE4 gene variant is a common genetic risk factor for AD and as taught by Satlin et al. and so treatment of said subject would improve symptoms.
Regarding instant claim 66, while copending and cited references do not demonstrate the combined method wherein a Aβ42/Aβ40 ratio after treatment is above 0.092, the combined method appears to be the same as that of instant claim 66 because the combined method administers the same reagents to the same subjects.
Regarding instant claim 67, it would be obvious to perform the above combined method, wherein the copending anti-protofibril antibody treatment is discontinued if measurements of blood Aβ42/Aβ40 ratio, upon treatment with a therapeutically effective dose of copending anti-protofibril antibody, does not indicate conversion to amyloid negative status so that the copending anti-Aβ protofibril antibody can be switched to another treatment to better manage AD in the subject.
Regarding instant claim 68, it would be obvious to perform the above combined method, wherein the treatment comprises an administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg/kg because this method is recited by copending claims and the intravenous administration would be one that is well known in the art for antibody administration. Further, regarding instant claim 69, the therapeutically effective dose is administered every 2 weeks would be an optimization of the dosing regimen that is obvious.
Regarding instant claim 70, it would be obvious to perform the above combined method, wherein the treatment comprises a subcutaneous administration of a therapeutically effective dose of the copending anti-Aβ protofibril antibody, because it would be obvious to try a different administration route since advantages of a subcutaneous injection include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, regarding instant claim 71, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is 720 mg, it would be obvious to try different doses when given subcutaneously in order to optimize the treatment. Further, regarding instant claim 72, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is administered weekly, it would be obvious to try different dosing intervals given subcutaneously in order to optimize the treatment. Even further, regarding instant claim 79, it would be obvious to have the subject switched to a maintenance dosing regimen comprising administration of a maintenance dose of the copending anti-Aβ protofibril antibody that is 50% of the subcutaneous administration of the anti-Aβ protofibril antibody, because once the subject is amyloid negative which indicates that the subject has been responsive, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 73, it would be obvious to perform the above combined method, wherein the frequency of administration is reduced after 18 months or 24 months of treatment because the treatment frequency can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in frequence of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 74, it would be obvious to perform the above combined method, wherein the dosage of the anti-Aβ protofibril antibody is reduced after 18 months or 24 months of treatment because the dosage can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in dosage of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 86, it would be obvious to perform the above combined method, and expect that the treatment delays clinical decline as measured by an ADAS-Cog as taught by Satlin et al.
Regarding instant claim 88, it would be obvious to perform the above combined method, and optimize the dosing regimen such that the method does not require a titration step prior to administering to the subject a first therapeutically effective dose of the anti-Aβ protofibril antibody because this could improve patient convenience and speed up the time to reach a full therapeutic effect.
Regarding instant claim 89, it would be obvious to perform the above combined method, wherein the subject has intermediate brain amyloid as measured by PET SUVr as taught by Schindler, prior to treatment with the copending anti-Aβ protofibril antibody because PET is an established method for diagnosis of AD base on the determination of brain amyloid status.
Regarding instant claim 90, it would be obvious to perform the above combined method, wherein the anti-Aβ protofibril antibody comprises the amino acid sequence of SEQ ID NOs: 5 and 6 as taught by Satlin et al. because an antibody comprising a variable heavy chain region, a heavy chain constant region, a variable light chain region and a light chain constant region would be an antibody Fab fragment that has the benefits of superior structural stability and a lower tendency to aggregate due to constant domain pairing and disulfide bonds compared to an Fv or scFv fragment.
Further, regarding instant claim 91, it would be obvious to perform the combined method of treating Alzheimer’s disease (AD) in a subject comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40 as taught by Schindler et al. wherein the subject had been administered the copending anti-amyloid β (Aβ) protofibril antibody; and b) administering a maintenance dosing regimen comprising a therapeutically effective dose of the copending anti-Aβ protofibril antibody to the subject, wherein the subject has an Aβ42/40 ratio that indicates amyloid negative status as taught by Schindler et al., because (1) Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis which can identify subjects that have amyloid negative status upon prior or previous AD treatment which translates to improved AD condition; (2) Satlin et al. teaches administrating a therapeutically effective amount of copending anti-Aβ protofibril antibody as a method for treating AD; and (3) a maintenance dosing regimen, usually a lower dose administered at longer intervals, can lower cost of therapy and can offer continued protection of the brain in a safe and stable manner.
Regarding instant claims 57 and 58, it would have been obvious to perform the above combined method, wherein the subject has AD or has early AD as taught by Satlin et al., because early treatment has the advantage of stopping brain changes early to protect the brain from progressive disease.
Regarding instant claim 59, it would be obvious to perform the above combined method, wherein the subject has preclinical Alzheimer’s disease as taught by Aisen et al., because Aisen et al. teaches that people with preclinical AD could benefit from treatment with the copending anti-Aβ monoclonal antibody, which is the alternative name for the copending antibody, as studied in the AHEAD A3 and A45 trials.
Regarding instant claim 60, it would be obvious to perform the above combined method, wherein the subject is cognitively normal but exhibits at least one biomarker of AD as taught in the DIAN-TU platform trial by Aisen et al. because there could be an advantage in starting preventative treatment of AD in the presymptomatic stage as taught by Aisen et al.
Regarding instant claim 75, it would be obvious to perform the above combined method, wherein after 18 months of treatment of the copending antibody, the subject is switched to a maintenance therapy because a maintenance therapy is usually a lower dose administered at longer intervals, therefore lowering cost of therapy while offering continued protection of the brain in a safe and stable manner.
Regarding instant claim 76, it would be obvious to perform the above combined method, wherein the subject is switched to a maintenance dosing regimen when a further Aβ42/40 ratio obtained after treatment indicates amyloid negative status because when the subject has shown responsiveness to the treatment dose based on the blood Aβ42/40 ratio, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 77, it would have been obvious to optimize the above combined method, wherein the maintenance dosing regimen comprises i.v. infusion of copending antibody at a dose of 10 mg/kg administered monthly because this would be an optimization of a treatment regimen and because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation.
Regarding instant claim 78, it would have been obvious to perform the above combined method, wherein the maintenance dosing regimen comprises of administration of copending antibody via subcutaneous route, and wherein the therapeutically effective dose of 360 mg, administered weekly, is an optimization of the dosing regimen because of the advantages of using subcutaneous injection over an intravenous (IV) route which include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, the dose of 360 mg and the frequency of weekly administration is obvious because these would be routine optimization of a dose based on route of administration and based on the responsiveness of the subject.
Regarding instant claim 82, it would have been obvious to optimize the above combined method, wherein the maintenance dose is optimized and administered at a dose and/or frequency selected to maintain an Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the value or parameter of “the maintenance dose” that results in the intended effect of “maintaining the Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status” in the instant claim is obvious.
Further, regarding instant claim 83, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455 because the additional medications have different mechanisms of action that can target the various biological manifestations of Alzheimer’s disease such that a multi-drug or multi-action approach can better protect brain function.
Regarding instant claim 80, it would have been obvious to perform the above combined method, wherein after 18 months of treatment of copending antibody the subject is switched to a maintenance dosing, and combine it with detecting the levels of plasma p-tau181 from the subject as taught by Rodriguez et al. and also optimize the timing of said detection to before switching to a maintenance dose to detect for a decrease in p-tau181 because Rodriguez et al. teaches that plasma p-tau181 is significantly higher in AD patients which translates to mean that a decrease in p-tau181 after antibody treatment indicates a response to the treatment and an improvement of the disease which would allow for a switch to maintenance dosing of the copending antibody. In addition, Rodriguez et al. teaches that using plasma p-tau181 as a biomarker to track disease progression and therapeutic response could have an advantage because plasma detection is more cost efficient compared to CSF testing and PET scan that are much more resource-intensive and more costly.
Regarding instant claim 84, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455, and wherein the additional AD medication is E2814 as taught by Roberts et al. because E2814 has the advantage of targeting a different pathological manifestation of Alzheimer’s disease which is the biomarker tau and because it can inhibit tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds, making the combination of copending anti-Aβ monoclonal antibody and anti-tau antibody E2814 a superior therapy for AD.
Regarding instant claim 85, it would have been obvious to perform the above combined method, wherein the method results in a reduction or a slowing of increase of the tau cerebrospinal fluid biomarker as taught by Swanson et al. because Swanson et al. teaches that BAN2401, the alternative name for the copending antibody, showed efficacy in significantly reducing brain amyloid in study patients.
Regarding instant claim 87, it would have been obvious to perform the above combined method, wherein said combined method further comprises monitoring for ARIA-E and/or ARIA-H by MRI as recited by copending claims because monitoring for ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) or ARIA-H (Amyloid-Related Imaging Abnormalities-Hemosiderin) allows for catching dangerous side effects of treatments early, so that the decision to pause or stop administration of antibody BAN2401 can be made to prevent severe or life-threatening brain damage as taught by Ferrero et al.
This is a provisional nonstatutory double patenting rejection.
Third NSDP: Application No. 18/688,264
Claims 50-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 64, 65, 67, 68, 69, 70, 71, 72 and 73 of copending Application No. 18/688,264 in view of Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659, Satlin et al. (US20190276560A1 Date Published 2019-09-12), Aisen et al. (J Prev Alzheimer’s Dis 8, 306–312; 2021; Available online 24 May 2021), NCT03887455 (Record History 2020-03-12), Rodriguez et al. (Acta Neuropathol. 2020 Sep;140(3):267-278), Roberts et al. (Alzheimer's & Dementia, 15: P1598-P1598; First published: 01 July 2019; AAIC Wednesday Poster Abstracts), Swanson et al. (Alzheimer's & Dementia, 14: P1668-P1668; First published: 01 July 2018) and Ferrero et al. (Translational Research & Clinical Interventions, (2016) 2: 169-176).
The copending claims are drawn to a method of treating Alzheimer’s disease comprising subcutaneously administering to a subject in need thereof a therapeutically effective amount of the same anti-Aβ protofibril antibody as the instant claims. However, the copending claims do not specifically also recite the method comprises: a) measuring a concentration of amyloid β 1-42 (Aβ42) and a concentration of amyloid β 1-40 (Aβ40) in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40(Aβ42/40 ratio); and b) administering said anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status; or administering subsequent treatments; or administering dosing regimens; or monitoring steps; or administering additional AD medication as recited by instant claims.
However, these deficiencies are rendered obvious by Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al.
The teachings of Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al. are discussed above.
However, it would be obvious to perform a combined method of treating Alzheimer’s disease (AD) of copending claims in view of cited references, in a subject having AD comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42/40 as taught by Schindler et al. wherein the subject has an Aβ42/40 ratio that indicates amyloid positive status also as taught by Schindler et al., and b) administering a treatment comprising a therapeutically effective amount of the anti-Aβ protofibril antibody as recited by copending claims, because Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis to identify subjects as candidates that would benefit from the administration of AD treatment with a reasonable predictability of success.
Regarding instant claim 51, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status, because determining a second Aβ42/Aβ40 ratio would identify whether the subject is amyloid positive, which would require further administration of a second treatment of a therapeutically effect dose of anti-Aβ protofibril antibody for effective and optimized management of disease when amyloid status remains positive. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claims 52 and 53, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a maintenance dose, and/or further maintenance doses, of the copending anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status, because determining a second Aβ42/Aβ40 ratio would identify the amyloid status of the subject and if the subject is amyloid negative, then a change in dose that to one that is a maintenance dose of anti-Aβ protofibril antibody can be made for effective and optimized management of disease when the amyloid status is no longer positive. Maintenance doses or maintenance dosing regimens usually comprise of lower dose and longer dosing intervals which has the advantage of reducing cost. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claim 54, it would have been obvious to perform the above combined method, wherein the Aβ42/40 ratio that indicates amyloid positive status is at most 0.1 because those patients with a Aβ42/40 ratio of 0.1 or below would be considered positive since Schindler et al. teaches Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status and that positive patients have an average ratio of 0.109 while negative patients have an average ratio of 0.119. Similarly, instant claims 55 and 56 are obvious because Schindler et al. teaches a ratio of 0.109 and lower for a Aβ42/40 ratio is indicative of positive amyloid status. Further, instant claim 65 is obvious because Schindler et al. teaches that Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status, therefore an elevated Aβ42/40 ratio after treatment with the copending anti-protofibril antibody indicates that the treatment has converted the subject from amyloid- positive to amyloid-negative status.
Regarding instant claim 61, it would have been obvious to perform the above combined method, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate likelihood as taught by Satlin et al. because it would be beneficial to treat the disease even when there is only mild cognitive impairment so that progression of disease can be delayed.
Regarding instant claims 62 and 64, it would have been obvious to perform the above combined method, wherein the amyloid-positive status is confirmed by a PET assessment as taught by Schindler et al., or wherein the concentrations of Aβ42 and Aβ40 used to obtain the Aβ42/40 ratio are measured using an LC MS/MS assay also as taught by Schindler et al. because PET assessment is a well-established technique used for determining levels of brain amyloid and because LC MS/MS assay is a routine technique in determining levels of biomarkers in bodily fluids obtained from subjects.
Regarding instant claim 63, it would have been obvious to perform the above combined method, wherein the subject is ApoE4-positive as recited in copending claims because it is well known in the art that ApoE4 gene variant is a common genetic risk factor for AD and as taught by Satlin et al. and so treatment of said subject would improve symptoms.
Regarding instant claim 66, while copending and cited references do not demonstrate the combined method wherein a Aβ42/Aβ40 ratio after treatment is above 0.092, the combined method appears to be the same as that of instant claim 66 because the combined method administers the same reagents to the same subjects.
Regarding instant claim 67, it would be obvious to perform the above combined method, wherein the copending anti-protofibril antibody treatment is discontinued if measurements of blood Aβ42/Aβ40 ratio, upon treatment with a therapeutically effective dose of anti-protofibril antibody, does not indicate conversion to amyloid negative status so that the anti-Aβ protofibril antibody can be switched to another treatment to better manage AD in the subject.
Regarding instant claim 68, it would be obvious to perform the above combined method, wherein the treatment comprises an intravenous administration of the copending anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject because this would be optimization of a dosing regimen which is common for administration of antibody therapeutics. Further, regarding instant claim 69, the therapeutically effective dose is administered every 2 weeks would be an optimization of the dosing regimen that is obvious.
Regarding instant claim 70, it would be obvious to perform the above combined method, wherein the treatment comprises a subcutaneous administration of a therapeutically effective dose of the copending anti-Aβ protofibril antibody as recited by copending claims, because of the advantages of a subcutaneous injection which includes convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, regarding instant claim 71, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is 720 mg, copending claims recite this dose and it would be obvious to try this dose when given subcutaneously in order to optimize the treatment. Further, regarding instant claim 72, wherein the therapeutically effective subcutaneous dose of the copending anti-Aβ protofibril antibody is administered weekly as recited by copending claims, it would be obvious to try and use this dosing interval in order to optimize the treatment. Even further, regarding instant claim 79, it would be obvious to have the subject switched to a maintenance dosing regimen comprising administration of a maintenance dose of the copending anti-Aβ protofibril antibody that is 50% of the subcutaneous administration of the anti-Aβ protofibril antibody as recited by copending claims, because once the subject is amyloid negative which indicates that the subject has been responsive, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 73, it would be obvious to perform the above combined method, wherein the frequency of administration is reduced after 18 months or 24 months of treatment as recited by copending claims because the treatment frequency can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in frequence of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 74, it would be obvious to perform the above combined method, wherein the dosage of the anti-Aβ protofibril antibody is reduced after 18 months or 24 months of treatment because the dosage can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in dosage of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 86, it would be obvious to perform the above combined method, and expect that the treatment delays clinical decline as measured by an ADAS-Cog as taught by Satlin et al.
Regarding instant claim 88, it would be obvious to perform the above combined method, and optimize the dosing regimen such that the method does not require a titration step prior to administering to the subject a first therapeutically effective dose of the anti-Aβ protofibril antibody because this could improve patient convenience and speed up the time to reach a full therapeutic effect.
Regarding instant claim 89, it would be obvious to perform the above combined method, wherein the subject has intermediate brain amyloid as measured by PET SUVr as taught by Schindler, prior to treatment with the copending anti-Aβ protofibril antibody because PET is an established method for diagnosis of AD base on the determination of brain amyloid status.
Regarding instant claim 90, it would be obvious to perform the above combined method, wherein the anti-Aβ protofibril antibody comprises the amino acid sequence of SEQ ID NOs: 5 and 6 as taught by Satlin et al. because an antibody comprising a variable heavy chain region, a heavy chain constant region, a variable light chain region and a light chain constant region would be an antibody Fab fragment that has the benefits of superior structural stability and a lower tendency to aggregate due to constant domain pairing and disulfide bonds compared to an Fv or scFv fragment.
Further, regarding instant claim 91, it would be obvious to perform the combined method of treating Alzheimer’s disease (AD) in a subject comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40 as taught by Schindler et al. wherein the subject had been administered the copending anti-amyloid β (Aβ) protofibril antibody; and b) administering a maintenance dosing regimen comprising a therapeutically effective dose of the copending anti-Aβ protofibril antibody to the subject, wherein the subject has an Aβ42/40 ratio that indicates amyloid negative status as taught by Schindler et al., because (1) Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis which can identify subjects that have amyloid negative status upon prior or previous AD treatment which translates to improved AD condition; (2) Satlin et al. teaches administrating a therapeutically effective amount of anti-Aβ protofibril antibody BAN2401 as a method for treating AD; and (3) a maintenance dosing regimen, usually a lower dose administered at longer intervals, can lower cost of therapy and can offer continued protection of the brain in a safe and stable manner.
Regarding instant claims 57 and 58, it would have been obvious to perform the above combined method, wherein the subject has AD or has early AD as taught by Satlin et al., because early treatment has the advantage of stopping brain changes early to protect the brain from progressive disease.
Regarding instant claim 59, it would be obvious to perform the above combined method, wherein the subject has preclinical Alzheimer’s disease as taught by Aisen et al., because Aisen et al. teaches that people with preclinical AD could benefit from treatment with the copending anti-Aβ monoclonal antibody, which is the alternative name for the copending antibody, as studied in the AHEAD A3 and A45 trials.
Regarding instant claim 60, it would be obvious to perform the above combined method, wherein the subject is cognitively normal but exhibits at least one biomarker of AD as taught in the DIAN-TU platform trial by Aisen et al. because there could be an advantage in starting preventative treatment of AD in the presymptomatic stage as taught by Aisen et al.
Regarding instant claim 75, it would be obvious to perform the above combined method, wherein after 18 months of treatment of the copending antibody, the subject is switched to a maintenance therapy as recited by copending claims. This is because a maintenance therapy is usually a lower dose administered at longer intervals, therefore lowering cost of therapy while offering continued protection of the brain in a safe and stable manner.
Regarding instant claim 76, it would be obvious to perform the above combined method, wherein the subject is switched to a maintenance dosing regimen when a further Aβ42/40 ratio obtained after treatment indicates amyloid negative status because when the subject has shown responsiveness to the treatment dose based on the blood Aβ42/40 ratio, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 77, it would have been obvious to optimize the above combined method, wherein the maintenance dosing regimen comprises i.v. infusion of copending antibody at a dose of 10 mg/kg administered monthly because this would be an optimization of the treatment regimen and because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation.
Regarding instant claim 78, it would have been obvious to perform the above combined method, wherein the maintenance dosing regimen comprises of administration of copending antibody via subcutaneous route, and wherein the therapeutically effective dose of 360 mg, administered weekly as recited by copending claims, because this would be an optimization of the dosing regimen and because of the advantages of using subcutaneous injection over an intravenous (IV) route which include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, the dose of 360 mg and the frequency of weekly administration is obvious because these would be routine optimization of a dose based on route of administration and based on the responsiveness of the subject.
Regarding instant claim 82, it would have been obvious to optimize the above combined method, wherein the maintenance dose is optimized and administered at a dose and/or frequency selected to maintain an Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the value or parameter of “the maintenance dose” that results in the intended effect of “maintaining the Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status” in the instant claim is obvious.
Further, regarding instant claim 83, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455 because the additional medications have different mechanisms of action that can target the various biological manifestations of Alzheimer’s disease such that a multi-drug or multi-action approach can better protect brain function.
Regarding instant claim 80, it would have been obvious to perform the above combined method, wherein after 18 months of treatment of copending antibody the subject is switched to a maintenance dosing as recited by copending claims, and combine it with detecting the levels of plasma p-tau181 from the subject as taught by Rodriguez et al. and also optimize the timing of said detection to before switching to a maintenance dose to detect for a decrease in p-tau181 because Rodriguez et al. teaches that plasma p-tau181 is significantly higher in AD patients which translates to mean that a decrease in p-tau181 after antibody treatment indicates a response to the treatment and an improvement of the disease. In addition, Rodriguez et al. teaches that using plasma p-tau181 as a biomarker to track disease progression and therapeutic response could have an advantage because plasma detection is more cost efficient compared to CSF testing and PET scan that are much more resource-intensive and more costly.
Regarding instant claim 84, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455, and wherein the additional AD medication is E2814 as taught by Roberts et al. because E2814 has the advantage of targeting a different pathological manifestation of Alzheimer’s disease which is the biomarker tau and because it can inhibit tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds, making the combination of copending anti-Aβ monoclonal antibody and anti-tau antibody E2814 a superior therapy for AD.
Regarding instant claim 85, it would have been obvious to perform the above combined method, wherein the method results in a reduction or a slowing of increase of the tau cerebrospinal fluid biomarker as taught by Swanson et al. because Swanson et al. teaches that BAN2401, the alternative name for the copending antibody, showed efficacy in significantly reducing brain amyloid in study patients.
Regarding instant claim 87, it would have been obvious to perform the above combined method, wherein said combined method further comprises monitoring for ARIA-E and/or ARIA-H by MRI as recited by copending claims because monitoring for ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) or ARIA-H (Amyloid-Related Imaging Abnormalities-Hemosiderin) allows for catching dangerous side effects of treatments early, so that the decision to pause or stop administration of antibody BAN2401 can be made to prevent severe or life-threatening brain damage as taught by Ferrero et al.
This is a provisional nonstatutory double patenting rejection.
Fourth NSDP: Application No. 18/720,518
Claims 50-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 67, 68, 70, 71, 72, 73, 74, 76, 77, 79 and 93 of copending Application No. 18/720,518 in view of Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659), Satlin et al. (US20190276560A1 Date Published 2019-09-12), Aisen et al. (J Prev Alzheimer’s Dis 8, 306–312; 2021; Available online 24 May 2021), NCT03887455 (Record History 2020-03-12), Rodriguez et al. (Acta Neuropathol. 2020 Sep;140(3):267-278), Roberts et al. (Alzheimer's & Dementia, 15: P1598-P1598; First published: 01 July 2019; AAIC Wednesday Poster Abstracts), Swanson et al. (Alzheimer's & Dementia, 14: P1668-P1668; First published: 01 July 2018) and Ferrero et al. (Translational Research & Clinical Interventions, (2016) 2: 169-176).
The copending claims are drawn to a method of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the same anti-Aβ protofibril antibody as the instant claims. However, the copending claims do not specifically also recite the method comprises: a) measuring a concentration of amyloid β 1-42 (Aβ42) and a concentration of amyloid β 1-40 (Aβ40) in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40(Aβ42/40 ratio); and b) administering said anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status; or administering subsequent treatments; or administering dosing regimens; or monitoring steps; or administering additional AD medication as recited by instant claims.
However, these deficiencies are rendered obvious by Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al.
The teachings of Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al. are discussed above.
However, it would be obvious to perform a combined method of treating Alzheimer’s disease (AD) of copending claims in view of cited references, in a subject having AD comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42/40 as taught by Schindler et al. wherein the subject has an Aβ42/40 ratio that indicates amyloid positive status also as taught by Schindler et al., and b) administering a treatment comprising a therapeutically effective amount of the copending anti-Aβ protofibril antibody, because Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis to identify subjects as candidates that would benefit from the administration of AD treatment with a reasonable predictability of success.
Regarding instant claim 51, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status, because determining a second Aβ42/Aβ40 ratio would identify whether the subject is amyloid positive, which would require further administration of a second treatment of a therapeutically effect dose of anti-Aβ protofibril antibody for effective and optimized management of disease when amyloid status remains positive. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claims 52 and 53, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a maintenance dose, and/or further maintenance doses, of the copending anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status, because determining a second Aβ42/Aβ40 ratio would identify the amyloid status of the subject and if the subject is amyloid negative, then a change in dose that to one that is a maintenance dose of anti-Aβ protofibril antibody can be made for effective and optimized management of disease when the amyloid status is no longer positive. Maintenance doses or maintenance dosing regimens usually comprise of lower dose and longer dosing intervals which has the advantage of reducing cost. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claim 54, it would have been obvious to perform the above combined method, wherein the Aβ42/40 ratio that indicates amyloid positive status is at most 0.1 because those patients with a Aβ42/40 ratio of 0.1 or below would be considered positive since Schindler et al. teaches Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status and that positive patients have an average ratio of 0.109 while negative patients have an average ratio of 0.119. Similarly, instant claims 55 and 56 are obvious because Schindler et al. teaches a ratio of 0.109 and lower for a Aβ42/40 ratio is indicative of positive amyloid status. Further, instant claim 65 is obvious because Schindler et al. teaches that Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status, therefore an elevated Aβ42/40 ratio after treatment with the copending anti-protofibril antibody indicates that the treatment has converted the subject from amyloid- positive to amyloid-negative status.
Regarding instant claim 61, it would have been obvious to perform the above combined method, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate likelihood as taught by Satlin et al. because it would be beneficial to treat the disease even when there is only mild cognitive impairment so that progression of disease can be delayed.
Regarding instant claims 62 and 64, it would have been obvious to perform the above combined method, wherein the amyloid-positive status is confirmed by a PET assessment as taught by Schindler et al., or wherein the concentrations of Aβ42 and Aβ40 used to obtain the Aβ42/40 ratio are measured using an LC MS/MS assay also as taught by Schindler et al. because PET assessment is a well-established technique used for determining levels of brain amyloid and because LC MS/MS assay is a routine technique in determining levels of biomarkers in bodily fluids obtained from subjects.
Regarding instant claim 63, it would have been obvious to perform the above combined method, wherein the subject has at least one copy of the ApoE4 gene as taught by Satlin et al. because it is well known in the art that ApoE4 gene variant is a common genetic risk factor for AD and as taught by Satlin et al. and so treatment of said subject would improve symptoms.
Regarding instant claim 66, while copending and cited references do not demonstrate the combined method wherein a Aβ42/Aβ40 ratio after treatment is above 0.092, the combined method appears to be the same as that of instant claim 66 because the combined method administers the same reagents to the same subjects.
Regarding instant claim 67, it would be obvious to perform the above combined method, wherein the copending anti-protofibril antibody treatment is discontinued if measurements of blood Aβ42/Aβ40 ratio, upon treatment with a therapeutically effective dose of anti-protofibril antibody, does not indicate conversion to amyloid negative status so that the anti-Aβ protofibril antibody can be switched to another treatment to better manage AD in the subject.
Regarding instant claim 68, it would be obvious to perform the above combined method, wherein the treatment comprises an intravenous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg/kg because this method is recited by copending claims. Further, regarding instant claim 69, the therapeutically effective dose is administered every 2 weeks as also recited by copending claims, would be an optimization of the dosing regimen that is obvious.
Regarding instant claim 70, it would be obvious to perform the above combined method, wherein the treatment comprises a subcutaneous administration of a therapeutically effective dose of the copending anti-Aβ protofibril antibody as recited by copending claims, because it would be obvious to try different administration routes and because of the advantages of a subcutaneous injection which include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, regarding instant claim 71, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is 720 mg, it would be obvious to try different doses when given subcutaneously in order to optimize the treatment. Further, regarding instant claim 72, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is administered weekly, it would be obvious to try different dosing intervals given subcutaneously in order to optimize the treatment. Even further, regarding instant claim 79, it would be obvious to have the subject switched to a maintenance dosing regimen comprising administration of a maintenance dose of the copending anti-Aβ protofibril antibody that is 50% of the subcutaneous administration of the anti-Aβ protofibril antibody, because once the subject is amyloid negative which indicates that the subject has been responsive, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 73, it would be obvious to perform the above combined method, wherein the frequency of administration is reduced after 18 months or 24 months of treatment because the treatment frequency can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in frequence of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 74, it would be obvious to perform the above combined method, wherein the dosage of the anti-Aβ protofibril antibody is reduced after 18 months or 24 months of treatment because the dosage can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in dosage of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 86, it would be obvious to perform the above combined method, and expect that the treatment delays clinical decline as measured by an ADAS-Cog as taught by Satlin et al.
Regarding instant claim 88, it would be obvious to perform the above combined method, and optimize the dosing regimen such that the method does not require a titration step prior to administering to the subject a first therapeutically effective dose of the anti-Aβ protofibril antibody because this could improve patient convenience and speed up the time to reach a full therapeutic effect.
Regarding instant claim 89, it would be obvious to perform the above combined method, wherein the subject has intermediate brain amyloid as measured by PET SUVr as taught by Schindler, prior to treatment with the anti-Aβ protofibril antibody taught by Satlin et al. because PET is an established method for diagnosis of AD base on the determination of brain amyloid status.
Regarding instant claim 90, it would be obvious to perform the above combined method, wherein the anti-Aβ protofibril antibody comprises the amino acid sequence of SEQ ID NOs: 5 and 6 as taught by Satlin et al. because an antibody comprising a variable heavy chain region, a heavy chain constant region, a variable light chain region and a light chain constant region would be an antibody Fab fragment that has the benefits of superior structural stability and a lower tendency to aggregate due to constant domain pairing and disulfide bonds compared to an Fv or scFv fragment.
Further, regarding instant claim 91, it would be obvious to perform the combined method of treating Alzheimer’s disease (AD) in a subject comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40 as taught by Schindler et al. wherein the subject had been administered the copending anti-amyloid β (Aβ) protofibril antibody; and b) administering a maintenance dosing regimen as recited by copending claims comprising a therapeutically effective dose of the copending anti-Aβ protofibril antibody to the subject, wherein the subject has an Aβ42/40 ratio that indicates amyloid negative status as taught by Schindler et al., because (1) Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis which can identify subjects that have amyloid negative status upon prior or previous AD treatment which translates to improved AD condition; (2) Satlin et al. teaches administrating a therapeutically effective amount of copending anti-Aβ protofibril antibody as a method for treating AD; and (3) a maintenance dosing regimen, usually a lower dose administered at longer intervals, can lower cost of therapy and can offer continued protection of the brain in a safe and stable manner.
Regarding instant claims 57 and 58, it would have been obvious to perform the above combined method, wherein the subject has AD or has early AD as taught by Satlin et al., because early treatment has the advantage of stopping brain changes early to protect the brain from progressive disease.
Regarding instant claim 59, it would be obvious to perform the above combined method, wherein the subject has preclinical Alzheimer’s disease as taught by Aisen et al., because Aisen et al. teaches that people with preclinical AD could benefit from treatment with the copending anti-Aβ monoclonal antibody, which is the alternative name for the copending antibody, as studied in the AHEAD A3 and A45 trials.
Regarding instant claim 60, it would be obvious to perform the above combined method, wherein the subject is cognitively normal but exhibits at least one biomarker of AD as taught in the DIAN-TU platform trial by Aisen et al. because there could be an advantage in starting preventative treatment of AD in the presymptomatic stage as taught by Aisen et al.
Regarding instant claim 75, it would be obvious to perform the above combined method, wherein after 18 months of treatment of the copending antibody, the subject is switched to a maintenance therapy as recited by copending claims. This is because a maintenance therapy is usually a lower dose administered at longer intervals, therefore lowering cost of therapy while offering continued protection of the brain in a safe and stable manner.
Regarding instant claim 76, it would be obvious to perform the above combined method, wherein the subject is switched to a maintenance dosing regimen as recited by copending claims when a further Aβ42/40 ratio obtained after treatment indicates amyloid negative status because when the subject has shown responsiveness to the treatment dose based on the blood Aβ42/40 ratio, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 77, it would have been obvious to optimize the above combined method, wherein the maintenance dosing regimen comprises i.v. infusion of copending antibody at a dose of 10 mg/kg and administered monthly as recited by copending claims, because this would be optimization of a treatment regimen and because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation.
Regarding instant claim 78, it would have been obvious to perform the above combined method, wherein the maintenance dosing regimen comprises of administration of copending antibody via subcutaneous route as recited by copending claims, and wherein the therapeutically effective dose of 360 mg, administered weekly, is an optimization of the dosing regimen because of the advantages of using subcutaneous injection which include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, the dose of 360 mg and the frequency of weekly administration is obvious because these would be routine optimization of a dose based on route of administration and based on the responsiveness of the subject.
Regarding instant claim 82, it would have been obvious to optimize the above combined method, wherein the maintenance dose is optimized and administered at a dose and/or frequency selected to maintain an Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the value or parameter of “the maintenance dose” that results in the intended effect of “maintaining the Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status” in the instant claim is obvious.
Further, regarding instant claim 83, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455 because the additional medications have different mechanisms of action that can target the various biological manifestations of Alzheimer’s disease such that a multi-drug or multi-action approach can better protect brain function.
Regarding instant claim 80, it would have been obvious to perform the above combined method, wherein after 18 months of treatment of copending antibody the subject is switched to a maintenance dosing as recited by copending claims, and combine it with detecting the levels of plasma p-tau181 from the subject as taught by Rodriguez et al. and also optimize the timing of said detection to before switching to a maintenance dose to detect for a decrease in p-tau181 because Rodriguez et al. teaches that plasma p-tau181 is significantly higher in AD patients which translates to mean that a decrease in p-tau181 after antibody treatment indicates a response to the treatment and an improvement of the disease. In addition, Rodriguez et al. teaches that using plasma p-tau181 as a biomarker to track disease progression and therapeutic response could have an advantage because plasma detection is more cost efficient compared to CSF testing and PET scan that are much more resource-intensive and more costly.
Regarding instant claim 84, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as taught by NCT03887455, and wherein the additional AD medication is E2814 as taught by Roberts et al. because E2814 has the advantage of targeting a different pathological manifestation of Alzheimer’s disease which is the biomarker tau and because it can inhibit tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds, making the combination of copending anti-Aβ monoclonal antibody and anti-tau antibody E2814 a superior therapy for AD.
Regarding instant claim 85, it would have been obvious to perform the above combined method, wherein the method results in a reduction or a slowing of increase of the tau cerebrospinal fluid biomarker as taught by Swanson et al. because Swanson et al. teaches that BAN2401, the alternative name for the copending antibody, showed efficacy in significantly reducing brain amyloid in study patients.
Regarding instant claim 87, it would have been obvious to perform the above combined method, wherein said combined method further comprises monitoring for ARIA-E and/or ARIA-H by MRI as recited by copending claims because monitoring for ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) or ARIA-H (Amyloid-Related Imaging Abnormalities-Hemosiderin) allows for catching dangerous side effects of treatments early, so that the decision to pause or stop administration of antibody BAN2401 can be made to prevent severe or life-threatening brain damage as taught by Ferrero et al.
This is a provisional nonstatutory double patenting rejection.
Fifth NSDP: Application No. 18/835,235
Claims 50-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 50, 57, 58, 59, 60, 61, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 and 85 of copending Application No. 18/835,235 in view of Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659), Satlin et al. (US20190276560A1 Date Published 2019-09-12), Aisen et al. (J Prev Alzheimer’s Dis 8, 306–312; 2021; Available online 24 May 2021), Rodriguez et al. (Acta Neuropathol. 2020 Sep;140(3):267-278), Roberts et al. (Alzheimer's & Dementia, 15: P1598-P1598; First published: 01 July 2019; AAIC Wednesday Poster Abstracts), Swanson et al. (Alzheimer's & Dementia, 14: P1668-P1668; First published: 01 July 2018) and Ferrero et al. (Translational Research & Clinical Interventions, (2016) 2: 169-176).
The copending claims are drawn to a method of treating Alzheimer’s disease in a subject having or suspected of having, comprising: a. measuring or having measured a level of p-tau181 in a blood sample obtained from the subject; and b. administering a treatment comprising a therapeutically effective dose of the same anti-amyloid β (Aβ) protofibril antibody as the instant claims to the subject having a p-tau181 level above a threshold that indicates amyloid positivity. However, the copending claims do not specifically recite the method comprises: a) measuring a concentration of amyloid β 1-42 (Aβ42) and a concentration of amyloid β 1-40 (Aβ40) in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40(Aβ42/40 ratio); and b) administering said anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status. In short, where the copending method recites measuring level of p-tau181 in a subject’s blood sample to indicate amyloid positivity, the instant method recites measuring a level of Aβ42 and Aβ40 in a blood a subject’s blood sample to determine the Aβ42/40 ratio that indicates amyloid positive or negative status.
However, these deficiencies are rendered obvious by Schindler et al., Satlin et al., Aisen et al., Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al.
The teachings of Schindler et al. Satlin et al., Aisen et al., Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al. are discussed above.
However, it would be obvious to perform a combined method of treating Alzheimer’s disease (AD) of copending claims in view of cited references, in a subject having AD comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42/40 as taught by Schindler et al. wherein the subject has an Aβ42/40 ratio that indicates amyloid positive status also as taught by Schindler et al., and b) administering a treatment comprising a therapeutically effective amount of the anti-Aβ protofibril antibody as taught by the copending claims, because Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis to identify subjects as candidates that would benefit from the administration of AD treatment with a reasonable predictability of success.
Regarding instant claim 51, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status, because determining a second Aβ42/Aβ40 ratio would identify whether the subject is amyloid positive, which would require further administration of a second treatment of a therapeutically effect dose of anti-Aβ protofibril antibody for effective and optimized management of disease when amyloid status remains positive. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claims 52 and 53, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a maintenance dose, and/or further maintenance doses, of the copending anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status, because determining a second Aβ42/Aβ40 ratio would identify the amyloid status of the subject and if the subject is amyloid negative, then a change in dose that to one that is a maintenance dose of anti-Aβ protofibril antibody can be made for effective and optimized management of disease when the amyloid status is no longer positive. Maintenance doses or maintenance dosing regimens usually comprise of lower dose and longer dosing intervals which has the advantage of reducing cost. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claim 54, it would have been obvious to perform the above combined method, wherein the Aβ42/40 ratio that indicates amyloid positive status is at most 0.1 because those patients with a Aβ42/40 ratio of 0.1 or below would be considered positive since Schindler et al. teaches Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status and that positive patients have an average ratio of 0.109 while negative patients have an average ratio of 0.119. Similarly, instant claims 55 and 56 are obvious because Schindler et al. teaches a ratio of 0.109 and lower for a Aβ42/40 ratio is indicative of positive amyloid status. Further, instant claim 65 is obvious because Schindler et al. teaches that Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status, therefore an elevated Aβ42/40 ratio after treatment with the copending anti-protofibril antibody indicates that the treatment has converted the subject from amyloid- positive to amyloid-negative status.
Regarding instant claim 61, it would have been obvious to perform the above combined method, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate likelihood as recited in the copending claims because it would be beneficial to treat the disease even when there is only mild cognitive impairment so that progression of disease can be delayed.
Regarding instant claims 62 and 64, it would have been obvious to perform the above combined method, wherein the amyloid-positive status is confirmed by a PET assessment as taught by Schindler et al., or wherein the concentrations of Aβ42 and Aβ40 used to obtain the Aβ42/40 ratio are measured using an LC MS/MS assay also as taught by Schindler et al. because PET assessment is a well-established technique used for determining levels of brain amyloid and because LC MS/MS assay is a routine technique in determining levels of biomarkers in bodily fluids obtained from subjects.
Regarding instant claim 63, it would have been obvious to perform the above combined method, wherein the subject has at least one copy of the ApoE4 gene as recited in copending claims because it is well known in the art that ApoE4 gene variant is a common genetic risk factor for AD and as taught by Satlin et al. and so treatment of said subject would improve symptoms.
Regarding instant claim 66, while copending and cited references do not demonstrate the combined method wherein a Aβ42/Aβ40 ratio after treatment is above 0.092, the combined method appears to be the same as that of instant claim 66 because the combined method administers the same reagents to the same subjects.
Regarding instant claim 67, it would be obvious to perform the above combined method, wherein the copending anti-protofibril antibody treatment is discontinued if measurements of blood Aβ42/Aβ40 ratio, upon treatment with a therapeutically effective dose of anti-protofibril antibody, does not indicate conversion to amyloid negative status so that the anti-Aβ protofibril antibody can be switched to another treatment to better manage AD in the subject.
Regarding instant claim 68, it would be obvious to perform the above combined method, wherein the treatment comprises an intravenous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject because this method is recited by copending claims. Further, regarding instant claim 69, the therapeutically effective dose is administered every 2 weeks would be an optimization of the dosing regimen that is obvious.
Regarding instant claim 70, it would be obvious to perform the above combined method, wherein the treatment comprises a subcutaneous administration of a therapeutically effective dose of the copending anti-Aβ protofibril antibody as recited by copending claims, because it would be obvious to try a different administration route to the intravenous infusion route also recited by copending claims since advantages of a subcutaneous injection over an intravenous (IV) route include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, regarding instant claim 71, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is 720 mg, copending claims recites this dose and so is made obvious. Further, regarding instant claim 72, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is administered weekly, copending claims recites this dose and so is made obvious. Even further, regarding instant claim 79, it would be obvious to have the subject switched to a maintenance dosing regimen comprising administration of a maintenance dose of the copending anti-Aβ protofibril antibody that is 50% of the subcutaneous administration of the copending anti-Aβ protofibril antibody, because copending claims recite this dosing regimen and also once the subject is amyloid negative which indicates that the subject has been responsive, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 73, it would be obvious to perform the above combined method, wherein the frequency of administration is reduced after 18 months or 24 months of treatment as recited by copending claims because the treatment frequency can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in frequence of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 74, it would be obvious to perform the above combined method, wherein the dosage of the anti-Aβ protofibril antibody is reduced after 18 months or 24 months of treatment as recited by copending claims because the dosage can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in dosage of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 86, it would be obvious to perform the above combined method, and expect that the treatment delays clinical decline as measured by an ADAS-Cog as taught by Satlin et al.
Regarding instant claim 88, it would be obvious to perform the above combined method, and optimize the dosing regimen such that the method does not require a titration step prior to administering to the subject a first therapeutically effective dose of the copending anti-Aβ protofibril antibody as recited by copending claims, because this could improve patient convenience and speed up the time to reach a full therapeutic effect.
Regarding instant claim 89, it would be obvious to perform the above combined method, wherein the subject has intermediate brain amyloid as measured by PET SUVr as taught by Schindler et al., prior to treatment with the copending anti-Aβ protofibril antibody because PET is an established method for diagnosis of AD base on the determination of brain amyloid status.
Regarding instant claim 90, it would be obvious to perform the above combined method, wherein the anti-Aβ protofibril antibody comprises the amino acid sequence of SEQ ID NOs: 9 and 10 as recited by copending claims because an antibody comprising a variable heavy chain region, a heavy chain constant region, a variable light chain region and a light chain constant region would be an antibody Fab fragment that has the benefits of superior structural stability and a lower tendency to aggregate due to constant domain pairing and disulfide bonds compared to an Fv or scFv fragment.
Further, regarding instant claim 91, it would be obvious to perform the combined method of treating Alzheimer’s disease (AD) in a subject comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40 as taught by Schindler et al. wherein the subject had been administered the copending anti-amyloid β (Aβ) protofibril antibody; and b) administering a maintenance dosing regimen as recited by copending claims comprising a therapeutically effective dose of the copending anti-Aβ protofibril antibody to the subject, wherein the subject has an Aβ42/40 ratio that indicates amyloid negative status as taught by Schindler et al., because (1) Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis which can identify subjects that have amyloid negative status upon prior or previous AD treatment which translates to improved AD condition; (2) Satlin et al. teaches administrating a therapeutically effective amount of the copending anti-Aβ protofibril antibody as a method for treating AD; and (3) a maintenance dosing regimen, usually a lower dose administered at longer intervals, can lower cost of therapy and can offer continued protection of the brain in a safe and stable manner.
Regarding instant claims 57 and 58, it would have been obvious to perform the above combined method, wherein the subject has AD or has early AD as taught by Satlin et al., because early treatment has the advantage of stopping brain changes early to protect the brain from progressive disease.
Regarding instant claim 59, it would be obvious to perform the above combined method, wherein the subject has preclinical Alzheimer’s disease as taught by Aisen et al., because Aisen et al. teaches that people with preclinical AD could benefit from treatment with the copending anti-Aβ monoclonal antibody, which is the alternative name for the copending antibody, as studied in the AHEAD A3 and A45 trials.
Regarding instant claim 60, it would be obvious to perform the above combined method, wherein the subject is cognitively normal but exhibits at least one biomarker of AD as recited in copending claims because there could be an advantage in starting preventative treatment of AD in the presymptomatic stage as taught by Aisen et al.
Regarding instant claim 75, it would be obvious to perform the above combined method, wherein after 18 months of treatment of the copending antibody, the subject is switched to a maintenance therapy as recited by copending claims. This is because a maintenance therapy is usually a lower dose administered at longer intervals, therefore lowering cost of therapy while offering continued protection of the brain in a safe and stable manner.
Regarding instant claim 76, it would be obvious to perform the above combined method, wherein the subject is switched to a maintenance dosing regimen when a further Aβ42/40 ratio as taught by Schindler et al. obtained after treatment indicates amyloid negative status because when the subject has shown responsiveness to the treatment dose based on the blood Aβ42/40 ratio, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 77, it would have been obvious to optimize the above combined method, wherein the maintenance dosing regimen comprises i.v. infusion of copending antibody at a dose of 10 mg/kg administered monthly as recited by copending claims, because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation.
Regarding instant claim 78, it would have been obvious to perform the above combined method, wherein the maintenance dosing regimen comprises of administration of copending antibody via subcutaneous route as recited by copending claims, and wherein the therapeutically effective dose of 360 mg, administered weekly as recited by copending claims, because this would be an optimization of the dosing regimen for advantages of using subcutaneous injection over an intravenous (IV) route which include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, the dose of 360 mg and the frequency of weekly administration is obvious because these would be routine optimization of a dose based on route of administration and based on the responsiveness of the subject.
Regarding instant claim 82, it would have been obvious to optimize the above combined method, wherein the maintenance dose is optimized and administered at a dose and/or frequency selected to maintain an Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the value or parameter of “the maintenance dose” that results in the intended effect of “maintaining the Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status” in the instant claim is obvious.
Further, regarding instant claim 83, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication as recited in copending claims because the additional medications have different mechanisms of action that can target the various biological manifestations of Alzheimer’s disease such that a multi-drug or multi-action approach can better protect brain function.
Regarding instant claim 80, it would have been obvious to perform the above combined method, wherein after 18 months of treatment of copending antibody the subject is switched to a maintenance dosing as recited by copending claims, and combine it with detecting the levels of plasma p-tau181 from the subject as recited in copending claims and also optimize the timing of said detection to before switching to a maintenance dose to detect for a decrease in p-tau181 because Rodriguez et al. teaches that plasma p-tau181 is significantly higher in AD patients which translates to mean that a decrease in p-tau181 after antibody treatment indicates a response to the treatment and an improvement of the disease. In addition, Rodriguez et al. teaches that using plasma p-tau181 as a biomarker to track disease progression and therapeutic response could have an advantage because plasma detection is more cost efficient compared to CSF testing and PET scan that are much more resource-intensive and more costly.
Regarding instant claim 84, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication and wherein the additional AD medication is E2814 as recited by copending claims because Roberts et al. teaches that E2814 has the advantage of targeting a different pathological manifestation of Alzheimer’s disease which is the biomarker tau and because it can inhibit tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds, making the combination of copending anti-Aβ monoclonal antibody and anti-tau antibody E2814 a superior therapy for AD.
Regarding instant claim 85, it would have been obvious to perform the above combined method, wherein the method results in a reduction or a slowing of increase of the tau cerebrospinal fluid biomarker as recited by copending claims because Swanson et al. teaches that BAN2401, the alternative name for the copending antibody, showed efficacy in significantly reducing brain amyloid in study patients.
Regarding instant claim 87, it would have been obvious to perform the above combined method, wherein said combined method further comprises monitoring for ARIA-E and/or ARIA-H by MRI as recited by copending claims because monitoring for ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) or ARIA-H (Amyloid-Related Imaging Abnormalities-Hemosiderin) allows for catching dangerous side effects of treatments early, so that the decision to pause or stop administration of antibody BAN2401 can be made to prevent severe or life-threatening brain damage as taught by Ferrero et al.
This is a provisional nonstatutory double patenting rejection.
Sixth NSDP: Application No. 19/133,053
Claims 50-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 40-44, 46, 47, 49, 50, 51 and 52 of copending Application No. 19/133,053 in view of Schindler et al. (Neurology 2019, vol. 93, no. 17, e1647-e1659, Satlin et al. (US20190276560A1 Date Published 2019-09-12), Aisen et al. (J Prev Alzheimer’s Dis 8, 306–312; 2021; Available online 24 May 2021), NCT03887455 (Record History 2020-03-12), Rodriguez et al. (Acta Neuropathol. 2020 Sep;140(3):267-278), Roberts et al. (Alzheimer's & Dementia, 15: P1598-P1598; First published: 01 July 2019; AAIC Wednesday Poster Abstracts), Swanson et al. (Alzheimer's & Dementia, 14: P1668-P1668; First published: 01 July 2018) and Ferrero et al. (Translational Research & Clinical Interventions, (2016) 2: 169-176).
The copending claims are drawn to a method of treating Alzheimer’s disease in a subject having or suspected of having, comprising administering to the subject a therapeutically effective dose of the same anti-Aβ protofibril antibody as the instant claims. However, the copending claims do not specifically also recite the method comprises: a) measuring a concentration of amyloid β 1-42 (Aβ42) and a concentration of amyloid β 1-40 (Aβ40) in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40(Aβ42/40 ratio); and b) administering said anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status; ; or administering subsequent treatments; or administering dosing regimens; or monitoring steps; or administering additional AD medication as recited by instant claims.
However, these deficiencies are rendered obvious by Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Roberts et al., Swanson et al. and Ferrero et al.
The teachings of Schindler et al., Satlin et al., Aisen et al., NCT03887455, Rodriguez et al., Swanson et al. and Ferrero et al. are discussed above.
However, it would be obvious to perform a combined method of treating Alzheimer’s disease (AD) of copending claims in view of cited references, in a subject having AD comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42/40 as taught by Schindler et al. wherein the subject has an Aβ42/40 ratio that indicates amyloid positive status also as taught by Schindler et al., and b) administering a treatment comprising a therapeutically effective amount of the anti-Aβ protofibril antibody as taught by the copending claims, because Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis to identify subjects as candidates that would benefit from the administration of AD treatment with a reasonable predictability of success.
Regarding instant claim 51, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a therapeutically effective dose of the anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid positive status, because determining a second Aβ42/Aβ40 ratio would identify whether the subject is amyloid positive, which would require further administration of a second treatment of a therapeutically effect dose of anti-Aβ protofibril antibody for effective and optimized management of disease when amyloid status remains positive. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claims 52 and 53, it would have been obvious to perform the above combined method that further comprises after administering the treatment: c) measuring a second concentration of Aβ42 and a second concentration of Aβ40 in a blood sample obtained from the subject to determine a second Aβ42/Aβ40 ratio; and d) administering a second treatment comprising a maintenance dose, and/or further maintenance doses, of the copending anti-Aβ protofibril antibody to the subject having an Aβ42/40 ratio that indicates amyloid negative status, because determining a second Aβ42/Aβ40 ratio would identify the amyloid status of the subject and if the subject is amyloid negative, then a change in dose that to one that is a maintenance dose of anti-Aβ protofibril antibody can be made for effective and optimized management of disease when the amyloid status is no longer positive. Maintenance doses or maintenance dosing regimens usually comprise of lower dose and longer dosing intervals which has the advantage of reducing cost. In addition, optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the “second measuring and second administering” in the instant claim is obvious.
Regarding instant claim 54, it would have been obvious to perform the above combined method, wherein the Aβ42/40 ratio that indicates amyloid positive status is at most 0.1 because those patients with a Aβ42/40 ratio of 0.1 or below would be considered positive since Schindler et al. teaches Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status and that positive patients have an average ratio of 0.109 while negative patients have an average ratio of 0.119. Similarly, instant claims 55 and 56 are obvious because Schindler et al. teaches a ratio of 0.109 and lower for a Aβ42/40 ratio is indicative of positive amyloid status. Further, instant claim 65 is obvious because Schindler et al. teaches that Aβ42/40 ratios of positive amyloid status are below those of negative amyloid status, therefore an elevated Aβ42/40 ratio after treatment with the copending anti-protofibril antibody indicates that the treatment has converted the subject from amyloid- positive to amyloid-negative status.
Regarding instant claims 57 and 58, it would have been obvious to perform the above combined method, wherein the subject has AD or has early AD as taught by Satlin et al., because early treatment has the advantage of stopping brain changes early to protect the brain from progressive disease.
Regarding instant claim 59, it would be obvious to perform the above combined method, wherein the subject has preclinical Alzheimer’s disease as taught by Aisen et al., because Aisen et al. teaches that people with preclinical AD could benefit from treatment with the copending anti-Aβ monoclonal antibody, which is the alternative name for the copending antibody, as studied in the AHEAD A3 and A45 trials.
Regarding instant claim 60, it would be obvious to perform the above combined method, wherein the subject is cognitively normal but exhibits at least one biomarker of AD as taught in the DIAN-TU platform trial by Aisen et al. because there could be an advantage in starting preventative treatment of AD in the presymptomatic stage as taught by Aisen et al.
Regarding instant claim 61, it would have been obvious to perform the above combined method, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate likelihood as taught by Satlin et al. because it would be beneficial to treat the disease even when there is only mild cognitive impairment so that progression of disease can be delayed.
Regarding instant claims 62 and 64, it would have been obvious to perform the above combined method, wherein the amyloid-positive status is confirmed by a PET assessment as taught by Schindler et al., or wherein the concentrations of Aβ42 and Aβ40 used to obtain the Aβ42/40 ratio are measured using an LC MS/MS assay also as taught by Schindler et al. because PET assessment is a well-established technique used for determining levels of brain amyloid and because LC MS/MS assay is a routine technique in determining levels of biomarkers in bodily fluids obtained from subjects.
Regarding instant claim 63, it would have been obvious to perform the above combined method, wherein the subject is an ApoE4 carrier as recited in copending claims because it is well known in the art that ApoE4 gene variant is a common genetic risk factor for AD and as taught by Satlin et al. and so treatment of said subject would improve symptoms.
Regarding instant claim 66, while copending and cited references do not demonstrate the combined method wherein a Aβ42/Aβ40 ratio after treatment is above 0.092, the combined method appears to be the same as that of instant claim 66 because the combined method administers the same reagents to the same subjects.
Regarding instant claim 67, it would be obvious to perform the above combined method, wherein the copending anti-protofibril antibody treatment is discontinued if measurements of blood Aβ42/Aβ40 ratio, upon treatment with a therapeutically effective dose of anti-protofibril antibody, does not indicate conversion to amyloid negative status so that the anti-Aβ protofibril antibody can be switched to another treatment to better manage AD in the subject.
Regarding instant claim 68, it would be obvious to perform the above combined method, wherein the treatment comprises an intravenous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject because this method is recited by copending claims. Further, regarding instant claim 69, the therapeutically effective dose is administered every 2 weeks is also recited by copending claims.
Regarding instant claim 70, it would be obvious to perform the above combined method, wherein the treatment comprises a subcutaneous administration of a therapeutically effective dose of the copending anti-Aβ protofibril antibody as recited by copending claims, because it would be obvious to try a different administration route to the intravenous infusion route also recited by copending claims since advantages of a subcutaneous injection over an intravenous (IV) route include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, regarding instant claim 71, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is 720 mg, copending claims recites this dose and so is made obvious. Further, regarding instant claim 72, wherein the therapeutically effective subcutaneous dose of the anti-Aβ protofibril antibody is administered weekly, copending claims recites this dose and so is made obvious. Even further, regarding instant claim 79, it would be obvious to have the subject switched to a maintenance dosing regimen comprising administration of a maintenance dose of the copending anti-Aβ protofibril antibody that is 50% of the subcutaneous administration of the copending anti-Aβ protofibril antibody, because once the subject is amyloid negative which indicates that the subject has been responsive, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 73, it would be obvious to perform the above combined method, wherein the frequency of administration is reduced after 18 months or 24 months of treatment as recited by copending claims because the treatment frequency can then be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in frequence of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 74, it would be obvious to perform the above combined method, wherein the dosage of the anti-Aβ protofibril antibody is reduced after 18 months or 24 months of treatment because dosage can be optimized to manage the subject according to the amyloid status and symptoms experienced by the subject post anti-Aβ protofibril antibody treatment for the specified period of months. In addition, a reduction in dosage of anti-Aβ protofibril antibody could mean a reduction in cost.
Regarding instant claim 86, it would be obvious to perform the above combined method, and expect that the treatment delays clinical decline as measured by an ADAS-Cog as taught by Satlin et al.
Regarding instant claim 88, it would be obvious to perform the above combined method, and optimize the dosing regimen such that the method does not require a titration step prior to administering to the subject a first therapeutically effective dose of the copending anti-Aβ protofibril antibody, because this could improve patient convenience and speed up the time to reach a full therapeutic effect.
Regarding instant claim 89, it would be obvious to perform the above combined method, wherein the subject has intermediate brain amyloid as measured by PET SUVr as taught by Schindler et al., prior to treatment with the copending anti-Aβ protofibril antibody because PET is an established method for diagnosis of AD base on the determination of brain amyloid status.
Regarding instant claim 90, it would be obvious to perform the above combined method, wherein the anti-Aβ protofibril antibody comprises the amino acid sequence of SEQ ID NOs: 5 and 6 as taught by Satlin et al. because an antibody comprising a variable heavy chain region, a heavy chain constant region, a variable light chain region and a light chain constant region would be an antibody Fab fragment that has the benefits of superior structural stability and a lower tendency to aggregate due to constant domain pairing and disulfide bonds compared to an Fv or scFv fragment.
Further, regarding instant claim 91, it would be obvious to perform the combined method of treating Alzheimer’s disease (AD) in a subject comprising: a) measuring a concentration of Aβ42 and a concentration of Aβ40 in a blood sample obtained from the subject to determine a ratio of Aβ42 to Aβ40 as taught by Schindler et al. wherein the subject had been administered the copending anti-amyloid β (Aβ) protofibril antibody; and b) administering a maintenance dosing regimen as recited by copending claims comprising a therapeutically effective dose of the copending anti-Aβ protofibril antibody to the subject, wherein the subject has an Aβ42/40 ratio that indicates amyloid negative status as taught by Schindler et al., because (1) Schindler et al. teaches that plasma Aβ42/40 ratio provides a highly accurate correlation to brain amyloidosis which can identify subjects that have amyloid negative status upon prior or previous AD treatment which translates to improved AD condition; (2) Satlin et al. teaches administrating a therapeutically effective amount of the copending anti-Aβ protofibril antibody as a method for treating AD; and (3) a maintenance dosing regimen, usually a lower dose administered at longer intervals, can lower cost of therapy and can offer continued protection of the brain in a safe and stable manner.
Regarding instant claim 75, it would be obvious to perform the above combined method, wherein after 18 months of treatment of the copending antibody, the subject is switched to a maintenance therapy because a maintenance therapy is usually a lower dose administered at longer intervals, therefore lowering cost of therapy while offering continued protection of the brain in a safe and stable manner.
Regarding instant claim 76, it would be obvious to perform the above combined method, wherein the subject is switched to a maintenance dosing regimen when a further Aβ42/40 ratio as taught by Schindler et al. obtained after treatment indicates amyloid negative status because when the subject has shown responsiveness to the treatment dose based on the blood Aβ42/40 ratio, it would be logical to switch to a maintenance dose which is a smaller amount of anti-Aβ protofibril antibody to keep a safe and steady level of the anti-Aβ protofibril antibody in the body of the subject. The smaller amount of anti-Aβ protofibril antibody would also be an added cost saving.
Regarding instant claim 77, it would have been obvious to optimize the above combined method, wherein the maintenance dosing regimen comprises i.v. infusion of copending antibody at a dose of 10 mg/kg as recited by copending claims, and optimized to be administered monthly because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation.
Regarding instant claim 78, it would have been obvious to perform the above combined method, wherein the maintenance dosing regimen comprises of administration of copending antibody via subcutaneous route, and wherein the therapeutically effective dose of 360 mg, administered weekly, because this would be an optimization of the dosing regimen for advantages of using subcutaneous injection over an intravenous (IV) route which include convenience and speed, as well as ease of having patient self-administer at home a subcutaneous injection that goes under the skin. In addition, the dose of 360 mg and the frequency of weekly administration is obvious because these would be routine optimization of a dose based on route of administration and based on the responsiveness of the subject.
Regarding instant claim 82, it would have been obvious to optimize the above combined method, wherein the maintenance dose is optimized and administered at a dose and/or frequency selected to maintain an Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status because optimization of treatment regimen is a result effective variable that can be determined by one or ordinary skill in the art with routine experimentation. Thus, the value or parameter of “the maintenance dose” that results in the intended effect of “maintaining the Aβ42/40 ratio in a blood sample from the subject that indicates amyloid negative status” in the instant claim is obvious.
Regarding instant claim 80, it would have been obvious to perform the above combined method, wherein after 18 months of treatment of copending antibody the subject is switched to a maintenance dosing as recited by copending claims, and combine it with detecting the levels of plasma p-tau181 from the subject as recited in copending claims and also optimize the timing of said detection to before switching to a maintenance dose to detect for a decrease in p-tau181 because Rodriguez et al. teaches that plasma p-tau181 is significantly higher in AD patients which translates to mean that a decrease in p-tau181 after antibody treatment indicates a response to the treatment and an improvement of the disease. In addition, Rodriguez et al. teaches that using plasma p-tau181 as a biomarker to track disease progression and therapeutic response could have an advantage because plasma detection is more cost efficient compared to CSF testing and PET scan that are much more resource-intensive and more costly.
Regarding instant claims 83 and 84, it would have been obvious to perform the above combined method, wherein the subject is simultaneously administered at least one additional AD medication and wherein the additional AD medication is E2814 as recited by copending claims because Roberts et al. teaches that E2814 has the advantage of targeting a different pathological manifestation of Alzheimer’s disease which is the biomarker tau and because it can inhibit tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds, making the combination of copending anti-Aβ monoclonal antibody and anti-tau antibody E2814 a superior therapy for AD. Further, administering additional therapies that have different mechanisms of action that can target the various biological manifestations of Alzheimer’s disease provides for a multi-drug or multi-action approach that can better protect brain function.
Regarding instant claim 85, it would have been obvious to perform the above combined method, wherein the method results in a reduction or a slowing of increase of the tau cerebrospinal fluid biomarker because Swanson et al. teaches that BAN2401, the alternative name for the copending antibody, showed efficacy in significantly reducing brain amyloid in study patients.
Regarding instant claim 87, it would have been obvious to perform the above combined method, wherein said combined method further comprises monitoring for ARIA-E and/or ARIA-H by MRI as recited by copending claims because monitoring for ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) or ARIA-H (Amyloid-Related Imaging Abnormalities-Hemosiderin) allows for catching dangerous side effects of treatments early, so that the decision to pause or stop administration of antibody BAN2401 can be made to prevent severe or life-threatening brain damage as taught by Ferrero et al.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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