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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
DETAILED ACTION
Election/Restrictions
Claims 1, 7-16, 19-22, 32-33, 38-39, 56, 69-70 and 73-74 are pending.
Applicant's election with traverse of Group I and the species of very low to moderate tau burden, preclinical or clinical AD, and posterolateral temporal lobe in the reply filed on 6/3/26 is acknowledged. Note that Applicant has elected both preclinical and clinical AD where Applicant was required to elect one such species. Preclinical and clinical AD are mutually exclusive. In the interest of furthering prosecution rather than delaying with a non-compliance notice, the Examiner will examine prodromal, mild, and clinical AD because prodromal and mild AD are considered part of clinical AD and so these three species articulated in the Applicant’s response are deemed to be the election. If Applicant intended to state that all four are obvious variations, such a statement will require the Examiner to also examine preclinical.
The traversal is on the ground(s) that:
Applicant argues that claim 15 of Ghanbari is not a method claim. While this is true, Applicant does not elaborate on how the teaching of the Aß antibody is irrelevant to the disclosed methods of Ghanbari nor does Applicant argue that the Aß antibody is not part of the special technical feature. The provision of examples of the teachings of Ghanbari does not exclude any other portions of the document.
Applicant argues that Ghanbari “does not disclose patient selection or stratification based on tau burden”. This is not persuasive because this is not the special technical feature. Instant claim 1 also does not claim patient stratification or selection based on tau burden. While Aß antibodies are claimed as being provided to subjects that have “been determined” as having certain tau burden, the claim administers the same antibody regimen regardless of what burden has been determined. Further, independent claims 38 and 39 only require that the subject has been determined as having “a tau burden” and does not require stratification based on the amount of that burden at all. To the extent that the regions are the stratifying criteria, this is not shared by all groups in the same way that not all claims require a certain SUVr. Group III (claims 32-33) does not require determining any amount of tau in any capacity. There is no shared amount of tau burden that forms a shared technical feature—the amount might be moderate, low, or very low, or might not be determined at all—and so the Examiner is correct in establishing that the shared feature is that tau is merely present since the claims do not require any shared amount and do not require the tau burden in any shared region.
Applicant argues that Ghanbari is an “or” claim but does not argue that administering the Aß antibody is not taught. Applicant appears to agree that Alzheimer’s patients have some amount of tau. Applicant argues that this does not constitute a method of treating a patient selected based on quantitatively defined tau burden. As above, the claims do not share a specific amount of tau as the shared technical feature, instead providing the same Aß antibody to a patient over a broad range of alternative values. Group III does not select the patient based on tau at all. Group IV selects the patient “based on” global tau, but this amount could be any value equal to or greater than zero. Group V similarly determine the tau burden but does not “stratify” the subjects in any way. The shared technical feature is that the subject has some level of tau, which is an inherent property of a human and so one administering the antibody has already determined this fact. This is not a special technical feature.
Applicant argues Ghanbari does not disclose:
Measuring tau burden quantitatively in a patient prior to or during anti-Aß antibody treatment.
There is no requirement in, e.g, claim 1 or claim 32 that tau burden is measured quantitively during treatment. As set forth below, Applicant’s use of “determined” is indefinite and so it is unclear if any such measurement is required by the claim. This is further supported by Applicant’s use of phrases such as “has been determined” which suggests the actual measurement is not part of the claimed method.
Any tau imaging methodology
Instant claim 1 does not appear to require tau imaging as part of the method. The measurement appears to be outside of the claim scope. Group III does not require any tau imaging.
Standardized uptake value ratios
Instant claim 1 requires administration to a subject that “has been determined” as having a certain tau burden. While the characterization of, e.g., moderate tau is defined in the specification, the claims do not appear to include such within the claim scope of, e.g., claim 1. Further, there is no SUVr which is required by the claims but rather represent a range of alternatives and so the shared feature is having tau burden at all, not a specific SUVr. Groups III, IV, and V do not require standardized uptake value ratios.
A specific framework for quantifying regional tau burden
This is not required by, e.g., claim 1 (Group I) nor any of Groups II-V and so is not a shared technical feature.
Any threshold values for tau burden
As evidenced by Applicant’s examples, these values are different among the groups (or not required at all) and so any specific value or threshold is not a shared technical feature.
Any relationship between pre-treatment tau burden level and treatment responsiveness
This is not required by any of the independent claims of the groups and so is not a shared technical feature.
Any method of selecting patients for anti-Aß therapy based on tau burden
As above, there is no specific burden which is shared nor do all of the groups require such selection (e.g., Group III does not determine tau burden at all) and so the shared feature is that the patient has some burden, which also as above would have been immediately recognized because this is a feature of AD.
Applicant argues the discovery that certain subjects respond better to Aß antibody therapy than others. None of the claims require any difference in antibody treatment between the groups and does not claim making any determinations about treatment for those with, e.g., high tau burden.
Applicant argues that Applicant’s discovery is not a generic observation about administering an antibody to a patient with Alzheimer’s disease. This is not persuasive because the treatment itself in claim 1 is a generic instruction to administer the same treatment to subjects irrespective to their tau burden. Aß antibodies are administered to subjects with very low, low, and moderate tau burden but also includes administration of the same therapy to those with high burden (comprises). Group III administers the antibody without ever determining the tau burden. Groups IV and V determine the burden but are generic to any obtained value.
Applicant argues donanemab is different than the antibody of Ghanbari. Since this antibody is absent from all claims, donanemab is not a shared technical feature.
Applicant argues the same special technical feature is shared among the groups:
Applicant argues Group I “applies the tau stratification to guide administration of anti-Aß therapy”. This is not a special technical feature because the stratification is not claimed in any way which would provide such guidance. As above, the claim scope includes administering the same antibody regiment to any subject with AD irrespective of tau burden. That the claim names certain alternatives is not commensurate with Applicant’s argument that the stratification “guides” administration in any way.
Applicant argues Group II applies tau-stratified patient selection to test treatment efficacy. Claim 22 applies the same treatment to those with very low, low, and moderate tau burden and does not contain any language which would preclude from doing the same to those with zero or high burden.
Applicant argues Group III “uses the same tau measurement framework” yet Group III (claims 32-33) contains no limitations at all regarding measuring tau.
Applicant argues Group IV uses the quantitative tau assessment to identify treatment candidates. The subjects of Group IV (claim 56) are selected regardless of the amount of tau determined as there are no limitations at all which would differentiate the selected subjects.
Applicant argues Group V uses longitudinal tau burden assessment to guide continuation of treatment. Only a single measurement of tau burden is claimed and so the method is not longitudinal and the only step is making that determination; the limitations of the preamble are an intended use (“for”) and do not add patentable weight to the claim because the body of the claim is complete in itself.
After further consideration, the restriction between “low to moderate” and “very low to moderate” tau burden is withdrawn. The election between clinical AD, prodromal AD, and mild AD is also withdrawn.
The requirement is still deemed proper. Therefore, the restriction is made FINAL.
Claims 22, 32-33, 56, and 69-70 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/3/26.
Claims 1, 7-16, 19-21, 38-39, and 73-74 are under examination.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code; see e.g., p. 46 L 25. 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 Rejections - 35 USC § 112
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 1, 7-16, 19-21, 38-39, and 73-74 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 1 requires a human subject that “has been determined” as having a certain tau burden. The specification at p.48-49 defines these burdens as measured by 18F-flortaucipir “based” quantitative analysis where quantitative analysis refers to calculation of SUVr and SUVr represents counts within a specific target region of interest in the brain.
The use of “has been” suggests that the determination is not a part of the instant method and occurs outside the scope of the claim. In other words, the claim would be infringed by administration of the antibody so long as the subject meets the tau burden criteria. The subject would have been determined by someone, somewhere, but the claim may or may not require the practitioner to be aware of this determination prior to administering the antibody. For example, the claim might be infringed if an Aß antibody is administered by one person to a subject when that subject has, at any point in the past, been determined as having a particular tau burden without the administrator knowing this fact. The past tense suggests that the subject receiving the antibody need not have any particular tau burden at the time of administration, only that sometime in the past they were determined as having that burden. However, the specification is broadly directed to using tau burden to inform the treatment decision, which makes the scope of the claim unclear.
This definition is further confused by claims such as claim 16. Claim 16 indicates the breadth of “has been determined” could be by way of any PET brain imaging, which is broader than the definition in the specification. This makes it unclear if the specific 18F-flortaucipir based quantitative analysis is required for the determination or, alternatively, that this is describing a property of the tau burden, e.g., if the 18F-flortaucipir based quantitative analysis was used, then the disclosed values would define the burden.
This confusion is further supported by claim 19. This claim explicitly claims that the tau burden “is determined” by any diagnostic that detects a biomarker for tau. This supports the above interpretation that the definition in the specification is indicating the values one would obtain when using that particular method but does not require that the tau burden be determined by that method. There is further confusion by using “is determined” in contrast to “has been determined”, making it further unclear whether or not the determination step is part of the claimed method. This use of “has been determined” and “determining” can be seen in instant claims 38 and 39, where the only difference is the use of these two phrases. This would support an interpretation where “has been determined” indicates the method of determination is not part of the claims, adding further confusion over the use of “is determined” in claim 19 that depends from claim 1.
Further, the use of “region of interest” is indefinite. A subject may have levels below 1.46 SUVr in one region but higher than 1.46 SUVr in another region. One interpretation would be that the subject has very low to moderate tau burden because at least one brain region meets these criteria. Another could determine that only the second brain region is “of interest” and therefore the subject does not have very low to moderate tau burden. This creates indefiniteness in the scope of the claim.
The instant specification defines “about” to be up to +/- 10%; the context of the claim does not suggest otherwise. Claim 12 recites “about an average of about 25 centiloids”. The phrase “about 25 centiloids” is an average of 22.5-27.5 centiloids (+-10% of 25). It is unclear if the “about an average” is meant to further increase this range to 20.25-30.25 (+- 10% of the 22.5-27.5 range), if the range is 20-30 (+- 20% of 25), if the range is 22.25-27.75 (10% plus 10% of 10%, i.e., +-11%), or some other value.
Therefore, claims 1, 7-16, 19-21, 38-39, and 73-74 are indefinite.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 7-16, 19-21, 38-39, and 73-74 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating Aß related diseases, does not reasonably provide enablement for preventing such diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: 1) nature of the invention, 2) breadth of claims, 3) amount of direction or guidance by the inventor, 4) relative skill of those in the art, 5) level of predictability in the art, 6) state of the prior art, 7) existence of working examples, and 8) quantity of the experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The nature of the invention is a method of treating or preventing human disease. The breadth includes preventing all diseases characterized by Aß deposits in the brain of a human subject, which includes Alzheimer’s disease and Down’s syndrome (instant claim 13). While skill in the art is high, predictability is low. The art currently does not recognize any drug or method that results in the complete prevention of Alzheimer’s disease. See for example Reitz (cited on form 892) that states “as the currently available drugs only slightly affect disease severity and progression, AD remains at present effectively untreatable” (p.2 C1) and Stanford (cited on form 892) that states "unfortunately, there are no currently available FDA-approved medications proven to delay or slow progression of the underlying brain degeneration and loss of synaptic connections that occurs in Alzheimer’s disease”. Where the goal is recognized as difficult and as-yet unrealized, the evidence supporting a claim that such a result is achievable must necessarily be strong. The instant specification does not provide any working examples of AD prevention nor does it provide adequate guidance on how to overcome the art-recognized difficult nature of this goal. One skilled in the art could not practice the method of the claims to achieve the result of prevention of AD as claimed.
The same is true of Down’s syndrome. Shmerling (form 892) states “there is no way to prevent Down syndrome” as well as “there is no treatment to reverse the genetic abnormality that causes Down syndrome”. The instant specification provides no examples of preventing Down syndrome. The specification does not provide any guidance on how an Aß antibody is meant to prevent or reverse the genetic abnormality that causes Down’s syndrome.
The quantity of experimentation is undue as there is no evidence nor scientific reasoning to expect that Applicant’s claimed Aß antibody would achieve the goals that the art recognizes as as-yet unachievable. This applies to claim encompassing broadly any Aß antibody administered by any means in any way (claim 1) as well as more specific claims such as claim 21.
Therefore, claims 1, 7-16, 19-21, 38-39, and 73-74 are not enabled for their full scope.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 15 and 16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 14 requires the subject is an early symptomatic AD patient. The specification at p.51 L6-7 uses “prodromal AD and mild dementia due to AD” as a synonym for early symptomatic AD. There does not appear to be any additional limitation provided by claim 15.
Claim 1 recites the subjects having conditions including “very low to moderate tau burden” and “low to moderate tau burden”. Claim 16 only provides definitions for those terms, e.g., very low to moderate is less than or equal to 1.46 SUVr as measured by PET brain imaging. The phrases are indefinite as described above. However, the claim language is broader than the definition provided by the specification itself. At p.48 starting at L25, “very low tau to moderate tau” burden is defined as less than or equal to 1.46 SUVr using 18F-flortaucipir based quantitative analysis. A similar definition for low to moderate tau starts at p.49 L1.
In one interpretation, the definition for the terms in claim 1 are already explicit in the specification and so reiterating those definitions in a dependent claim does not serve as an additional limitation. Further, claim 16 recites that the SUVr may be performed by any form of PET brain imaging, which is broader than the explicit 18F-flortaucipir based quantitative analysis required by the special definition in the specification.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 7-16, 19-20, and 73 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by DeMattos (IDS 2/8/24 NPL citation 12) as evidenced by Anonymous (IDS 2/8/24 NPL citation 3; herein ClinicalTrials).
Regarding claim 1, DeMattos teaches determining a target population based on tau PET criteria (p.10) where the tau criteria is having low to medium tau burden defined as SUVR 1.15-1.36 as determined by flortaucipir PET(p.9). This meets the limitations of “has been determined as having low to moderate tau burden”, which itself is wholly contained within and therefore also anticipates “has been determined as having very low to moderate tau burden”. In other words, the determination that the subject has moderate tau burden meets the limitations of both groups.
While not explicitly human, DeMattos refers to the subjects as “patients” who “reported” their memory function (p.9) and “volunteers” (p.8), clearly evidencing that the subjects were human.
After having determined the human subjects have low to moderate tau burden, DeMattos teaches administering LY3002813, also called N3pG mAb (p.10). This is an anti-Aß antibody as taught by DeMattos (p.3). The subjects are “early symptomatic [Alzheimer’s disease]”, which is a disease characterized by Aß deposits in the brain; see, e.g., instant claim 13.
Neither the instant claim nor the instant specification define “an effective amount”. DeMattos teaches administering the antibody as a “treatment” and evaluates the “efficacy” (p.10). DeMattos teaches the mechanism by which the antibody is meant to function (p.2), including “block local toxicity”. DeMattos teaches the antibody clear existing Aß plaques (p.3) along with other therapeutic benefits (p.6-7). This evidence is sufficient to conclude that the amount of Aß antibody administered meets the limitations of “an effective amount” as instantly claimed.
DeMattos refers to flortaucipir PET tau analysis but does not explicitly state this is 18F-flortaucipir. First, as above, it is unclear whether or not measurement using 18F-flortaucipir is required. Under an interpretation that the definition in the specification is describing a property, this property is inherent. Under the interpretation where the measurement is required, DeMattos used 18F-flortaucipir in the determination step as evidenced by ClinicalTrials, which discusses the trial disclosed in DeMattos (NCT03367403) used 18F flortaucipir for the eligibility criteria.
These teachings anticipate each and every limitation of instant claim 1.
Regarding claim 7, the instant specification defines “treating” broadly to include embodiments such as slowing a symptom of the disease. The specification does not define any particular amount of time required to “treat”. DeMattos teaches administering a treatment comprising the Aß antibody for 80 weeks, which is considered to meet the requirements of a sufficient duration to treat the disease.
Regarding claim 8, the claim is directed to results of the administration step. As DeMattos meets the limitations of this administration step, these results must necessarily follow. This is further supported by the teachings of DeMattos regarding the effects of the antibody, such as increased plaque removal.
Regarding claim 9, DeMattos teaches measuring the effects of treatment by amyloid PET (p.10), which is imaged in the brain; see, e.g., p.7.
Regarding claim 10, DeMattos does not teach that 80 weeks of treatment reduces the Aß deposits in the brain by about 20% (at least 18%; see definition of “about” on p.49 of the specification). However, the disclosure of the efficacy of the antibody in clearing plaques discussed above provides sufficient evidence to conclude that this limitation is met.
Regarding claim 11, the claim is directed to results of the administration step. As DeMattos meets the limitations of this administration step, these results must necessarily follow. This is further supported by the teachings of DeMattos regarding the effects of the antibody, such as increased plaque removal.
Regarding claim 12, DeMattos does not teach that 80 weeks of treatment reduces the Aß deposits in the brain by 22.5-110 centiloids (+-10% of 25-100). However, the disclosure of the efficacy of the antibody in clearing plaques discussed above provides sufficient evidence to conclude that this limitation is met. In particular, also see DeMattos p.7 which discloses the reduction of Aß plaques in terms of centiloid change including values over 40.
Regarding claim 13, DeMattos teaches selecting subjects who are “early symptomatic AD”, which meets the limitation of prodromal AD (instant specification p.51 L6-7). This also meets the limitations of clinical AD; see instant specification p.47: “a diagnosed stage of AD” where “early symptomatic” has been diagnosed and is a stage and where prodromal is also considered such a stage.
Regarding claim 14, an early symptomatic AD patient is anticipated as above.
Regarding claim 15, the subject having prodromal AD is anticipated as above. DeMattos also teaches mild dementia is a symptom of AD (p.11). DeMattos does not explicitly teach that “early symptomatic AD” patients are both prodromal and have mild dementia. However, prodromal describes a subject showing the early signs or symptoms of a disease and the instant specification uses the limitations of claim 15 as a synonym for the phrase “early symptomatic AD” (p.51). A subject displaying early symptoms such as dementia would also be mild as opposed to the later presentation of moderate or severe dementia as the disease progresses. The evidence supports the conclusion that the subjects of DeMattos meets the limitations of instant claim 15.
Regarding claim 16, DeMattos teaches the subjects have SUVr values of 1.15 and 1.36 according to Tau PET, which meets the instant limitations of both less than or equal to 1.46 as well as 1.10-1.46.
Regarding claim 19, tau burden is determined by PET brain imaging as discussed above.
Regarding claim 20, DeMattos administers LY3002813 (N3pG mAb), which is also known as donanemab (as evidenced by ClinicalTrials p.3) and is an anti-N3pGlu Aß antibody.
Regarding claim 73, this claim is broader than claim 1 and is anticipated for the same reasons. Briefly, DeMattos teaches determining a subject having low to moderate tau burden and then administering an effective amount of an anti-Aß antibody.
Further, claim 73 is anticipated by p.9 of DeMattos. DeMattos determines “whether” a human subject has very low/low to moderate tau burden. In the case of the first image (“no tau”) the answer is that the subject does not have such a burden. The claim contains limitations if they are determined to have a specific burden but no limitations regarding a subject “determined” to not have those burdens, i.e., when the “if” clause is not satisfied. As such, determining that the subject does not have very low/low to moderate tau burden (“whether”) anticipates the claim as there are no steps after this determination required.
Therefore, claims 1, 7-16, 19-20, and 73 are anticipated by DeMattos. Further note that the pattern in Fleisher (discussed below in the §103 rejection of claims 38 and 39) appears to be the same as in DeMattos p.9, suggesting that the global tau measurement in low/medium tau is also a determination of tau burden in the PLT. If any portion of the DeMattos image is within the posterolateral temporal lobe, then this meets the limitations of establishing “a tau burden” in this region. However, the image in the supplied copy coupled with the information in Demattos is insufficient to conclude this is the case and so these claims were not included in the anticipation rejection.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 7-16, 19-21, and 73 is/are rejected under 35 U.S.C. 103 as being unpatentable over DeMattos (IDS 2/8/24 NPL citation 12) in view of Anonymous (IDS 2/8/24 NPL citation 3; herein ClinicalTrials).
Regarding claim 1, DeMattos teaches determining a target population based on tau PET criteria (p.10) where the tau criteria is having low to medium tau burden defined as SUVR 1.15-1.36 as determined by flortaucipir PET(p.9). This meets the limitations of “has been determined as having low to moderate tau burden”, which itself is wholly contained within and therefore also anticipates “has been determined as having very low to moderate tau burden”. In other words, the determination that the subject has moderate tau burden meets the limitations of both groups.
ClinicalTrials is also directed to treating patients with an anti-Aß antibody called donanemab, which is also known as LY3002813 and is the same antibody in DeMattos. ClinicalTrials also teaches using flortaucipir tau PET prior to administration (see inclusion criteria p.6-7).
It would have been obvious to combine the teachings of DeMattos and Clinical trials because the two documents describe the same method (NCT03367403). Both teach determining the tau burden by tau PET prior to administration of the antibody and one would have found it obvious to select those with low or moderate burden because DeMattos teaches performing the method on these subjects. It would have been obvious to treat with an anti-Aß antibody because this step is taught by both DeMattos and ClinicalTrials.
While not explicitly human, DeMattos refers to the subjects as “patients” who “reported” their memory function (p.9) and “volunteers” (p.8), clearly evidencing that the subjects were human. This is also true of ClinicalTrials (“participants” p.1; using the MMSE which requires naming objects and following written commands p.4; participant reported memory function p.6).
After having determined the human subjects have low to moderate tau burden, DeMattos teaches administering LY3002813, also called N3pG mAb (p.10). This is an anti-Aß antibody as taught by DeMattos (p.3). The subjects are “early symptomatic [Alzheimer’s disease]”, which is a disease characterized by Aß deposits in the brain; see, e.g., instant claim 13. ClinicalTrials also treats those with AD and includes those with “gradual” changes (p.6) for the assessment of the Aß antibody in subjects with “early symptomatic” AD (p.1). ClinicalTrials teaches the same Aß antibody and so it would have been obvious to administer an Aß antibody to treat a disease characterized by Aß because both documents suggest doing so.
Neither the instant claim nor the instant specification define “an effective amount”. DeMattos teaches administering the antibody as a “treatment” and evaluates the “efficacy” (p.10). DeMattos teaches the mechanism by which the antibody is meant to function (p.2), including “block local toxicity”. DeMattos teaches the antibody clear existing Aß plaques (p.3) along with other therapeutic benefits (p.6-7). This evidence is sufficient to conclude that the amount of Aß antibody administered meets the limitations of “an effective amount” as instantly claimed. Similarly, ClinicalTrials suggests specific doses over the course of 72+ weeks (p.3) to evaluate the efficacy of the antibody.
It would have been obvious to one of ordinary skill in the art to administer an amount of the antibody effective to treat AD. The combination of references teaches administering the antibody for this purpose (treating AD), provides mechanisms and results providing a reasonable expectation of this outcome, and one of ordinary skill in the art set to treat a disease would have found it obvious to use an effective amount because an ineffective amount would not achieve the desired goal.
DeMattos refers to flortaucipir PET tau analysis but does not explicitly state this is 18F-flortaucipir. As above, it is unclear whether or not measurement using 18F-flortaucipir is required. Under an interpretation that the definition in the specification is describing a property, this property is inherent. Under the interpretation where the measurement is required, DeMattos used 18F-flortaucipir in the determination step as taught by ClinicalTrials, which discusses the trial disclosed in DeMattos (NCT03367403) used 18F flortaucipir for the eligibility criteria. ClinicalTrials suggests the same method of establishing tau burden and so would have been an obvious choice to one of ordinary skill in the art.
These teachings and rationale would have made obvious instant claim 1 when considered as a whole.
Regarding claim 7, the instant specification defines “treating” broadly to include embodiments such as slowing a symptom of the disease. The specification does not define any particular amount of time required to “treat”. DeMattos teaches administering a treatment comprising the Aß antibody for 80 weeks, which is considered to meet the requirements of a sufficient duration to treat the disease. ClinicalTrials administers the antibody for 72+ weeks, which is also considered to meet the requirements and so it would have been obvious to one of ordinary skill in the art to utilize these known administration regimens to treat AD. Additionally, it would have been obvious to a person of ordinary skill in the art at the time of filing to continue a therapeutic treatment until the disease is treated. See MPEP 2141(II)(C): "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. Treating a person for a disease until such time as the disease is treated is one such inference or creative step.
Regarding claim 8, the claim is directed to results of the administration step. As DeMattos/ClinicalTrials meets the limitations of this administration step, these results must necessarily follow. This is further supported by the teachings of DeMattos regarding the effects of the antibody, such as increased plaque removal.
Regarding claim 9, DeMattos teaches measuring the effects of treatment by amyloid PET (p.10), which is imaged in the brain; see, e.g., p.7. ClinicalTrials also teaches measuring the effects of treatment by amyloid PET (point 5 on p.5). Since both documents teach measuring the reduction of Aß deposits in this manner, such a step would have been obvious.
Regarding claim 10, DeMattos does not teach that 80 weeks of treatment reduces the Aß deposits in the brain by about 20% (at least 18%; see definition of “about” on p.49 of the specification). Similarly, ClinicalTrials does not teach that 72+ weeks of treatment reduces the Aß deposits in the brain by at least 18%, though does teach evaluating the efficacy of the antibody by measuring the reduction in plaques (p.5). The disclosure of the efficacy of the antibody in clearing plaques discussed above provides sufficient evidence to conclude that this limitation is met. Additionally, this would have been obvious to a person of ordinary skill in the art at the time of filing to continue a therapeutic treatment until the pathology of the disease is reduced. See MPEP 2141(II)(C): "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. The art teaches Aß deposits (plaques) in the brain are deleterious and that the Aß antibody of the method reduces these plaques. Continuing to reduce these plaques as much as possible, including 18-100%, is one such inference or creative step.
Regarding claim 11, the claim is directed to results of the administration step. As DeMattos/ClinicalTrials meets the limitations of this administration step, these results must necessarily follow. This is further supported by the teachings of DeMattos regarding the effects of the antibody, such as increased plaque removal.
Regarding claim 12, DeMattos does not teach that 80 weeks of treatment reduces the Aß deposits in the brain by 22.5-110 centiloids (+-10% of 25-100). Similarly, ClinicalTrials does not teach that 72+ weeks of treatment reduces the Aß deposits in the brain by at least 18%, though does teach evaluating the efficacy of the antibody by measuring the reduction in plaques (p.5). The disclosure of the efficacy of the antibody in clearing plaques discussed above provides sufficient evidence to conclude that this limitation is met. In particular, also see DeMattos p.7 which discloses the reduction of Aß plaques in terms of centiloid change including values over 40. Additionally, this would have been obvious to a person of ordinary skill in the art at the time of filing to continue a therapeutic treatment until the pathology of the disease is reduced. See MPEP 2141(II)(C): "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. The art teaches Aß deposits (plaques) in the brain are deleterious and that the Aß antibody of the method reduces these plaques. Continuing to reduce these plaques as much as possible, including by at least 22.5 centiloids, is one such inference or creative step. Note that claim 12 does not require measurement of the plaques, only that the plaques are reduced by the claimed amount. The art does, however, teach such measurement as above.
Regarding claim 13, DeMattos teaches selecting subjects who are “early symptomatic AD” as above, as does ClinicalTrials (p.1), which meets the limitation of prodromal AD (instant specification p.51 L6-7). This also meets the limitations of clinical AD; see instant specification p.47: “a diagnosed stage of AD” where “early symptomatic” has been diagnosed and is a stage and where prodromal is also considered such a stage. It would have been obvious to select such a subject because both documents teach selecting such a subject.
Regarding claim 14, an early symptomatic AD patient would have been obvious as above.
Regarding claim 15, the subject having prodromal AD would have been obvious as above. DeMattos also teaches mild dementia is a symptom of AD (p.11). Neither DeMattos nor ClinicalTrials explicitly teach that “early symptomatic AD” patients are both prodromal and have mild dementia. However, prodromal describes a subject showing the early signs or symptoms of a disease and the instant specification uses the limitations of claim 15 as a synonym for the phrase “early symptomatic AD” (p.51). A subject displaying early symptoms such as dementia would also be mild as opposed to the later presentation of moderate or severe dementia as the disease progresses. As the combination suggest selecting those subjects in the early stages of the disease, it would have been obvious to include those prodromal subjects that present with mild dementia due to AD. Additionally, this would have been obvious to a person of ordinary skill in the art at the time of filing to select a subject who is both prodromal and has mild AD dementia. The art teaches selecting those who are “early symptomatic”, which is prodromal as discussed above. DeMattos also teaches another study where the subjects have “mild AD dementia” (p.11), making it obvious to include subjects having both conditions under an interpretation where mild dementia is not an inherent part of “early symptomatic”.
Regarding claim 16, DeMattos teaches the subjects have SUVr values of 1.15 and 1.36 according to Tau PET, which meets the instant limitations of both less than or equal to 1.46 as well as 1.10-1.46. It would have been obvious to select such subjects for the reasons above.
Regarding claim 19, tau burden is determined by PET brain imaging as discussed above.
Regarding claim 20, DeMattos administers LY3002813 (N3pG mAb), which is also known as donanemab as taught by ClinicalTrials (p.3) and is an anti-N3pGlu Aß antibody. This would have been an obvious choice because both documents teach using the same antibody to treat AD.
Regarding claim 21, DeMattos teaches administering LY3002813 (donanemab) but does not teach specific doses. ClinicalTrials teaches administration of donanemab at 700 mg (one or more first doses of about 700 mg) every 4 weeks (about once every 4 weeks). ClinicalTrials teaches following that dose with a dose of 1400 mg (one or more second doses of greater than about 700mg) every four weeks (Q4W). As every dose is administered once every 4 weeks, it would have been obvious that the second dose amount follows the first dose amount by 4 weeks as well. It would have been obvious to use this dosing regimen because the art teaches this as an acceptable regimen for donanemab.
Regarding claim 73, this claim is broader than claim 1 and would have been obvious for the same reasons. Briefly, DeMattos/ClinicalTrials teaches determining a subject having low to moderate tau burden and then administering an effective amount of an anti-Aß antibody.
Therefore, claims 1, 7-16, 19-21, and 73 would have been obvious.
Claim(s) 38 and 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over DeMattos (IDS 2/8/24 NPL citation 12)/ Anonymous (IDS 2/8/24 NPL citation 3; herein ClinicalTrials) as applied to claims 1, 7-16, 19-21, and 73 above, and further in view of Fleisher (IDS 2/8/24 NPL citation 27).
The discussion of the art and claims 1, 7-16, 19-21, and 73 are discussed above and incorporated herein. DeMattos evaluates a global tau burden (p.9). ClinicalTrials teaches using Tau PET to quantify the “spaciotemporal accumulation pattern of tau”, which suggests measuring tau burden in specific regions of the brain (“spacio”/spatial). ClinicalTrials also teaches measurement in 14 brain regions specifically (p.6). Neither reference explicitly teaches determining tau burden in the posterolateral temporal lobe.
Fleisher teaches the PLT (posterior lateral temporal lobe of the brain) represents an early AD tau pattern (p.8). Fleisher presents this pattern in both “low tau” and “intermediate tau” (p.9).
One of ordinary skill in the art would have found it obvious to establish tau burden because DeMattos and ClinicalTrials both do so to select subjects for treatment. Those subjects are taught as early symptomatic AD with low to moderate tau burden as discussed above. One of ordinary skill in the art would have found it obvious to establish a tau burden in the PLT because Fleisher teaches this occurs early in AD and is found in low to intermediate/moderate tau burden brains, which are the same subjects as DeMattos/ClinicalTrials.
It would have been obvious to proceed to the Aß antibody administration step irrespective of whether one performed the determination themselves (claim 39) or if the tau burden had been previously established by another (claim 38) because in either case the subject is one fit for Aß antibody treatment based on the combined teachings.
Therefore, claims 1, 7-16, 19-21, 38-39 and 73 would have been obvious.
Claim(s) 74 is/are rejected under 35 U.S.C. 103 as being unpatentable over DeMattos (IDS 2/8/24 NPL citation 12)/ Anonymous (IDS 2/8/24 NPL citation 3; herein ClinicalTrials) as applied to claims 1, 7-16, 19-21, and 73 above, and further in view of Ishibai (IDS 3/7/24 NPL citation 4).
The discussion of the art and claims 1, 7-16, 19-21, and 73 are discussed above and incorporated herein. Neither reference teaches taking the APOE status of the subject into account.
Regarding claim 74, nevertheless it would have been obvious to select a subject that has low/moderate tau (discussed above) as well as having one or two APOE e4 alleles.
It would have been obvious to determine the APOE e4 status of the subject. Ishibai is concerned with administering the same antibody as DeMattos/ClinicalTrials (donanemab) to treat AD. Ishibai also uses PET imaging (p.3), selects those with early symptomatic AD (p.4; title), and teaches reduction of Aß plaques measured in centiloids (p.15). Further, Ishibai teaches establishing the APOE e4 carrier status of the subjects (p.6). These are the subjects who were treated with the antibody and so it would have been obvious to obtain the same demographic information—including APOE e4 status—because of the teachings of Ishibai.
Regarding claim 74, an APOE e4 carrier must have either one or two alleles of APOE e4 because humans have two alleles and being a carrier means having at least one. As these subjects were then administered the anti-Aß antibody, the combination of references arrives at the embodiment of determining whether the subject has very low/low/moderate tau burden (DeMattos/ClinicalTrials) and determining whether the subject has one or two alleles of APOE e4 (Ishibai) and then administering an anti-Aß antibody.
Regarding claims 73 and 74, the combination also arrives at the embodiment of determining whether the subject has zero (DeMattos/ClinicalTrials) and determining whether the subject has zero alleles (non-carrier; Ishibai). The claim uses the language “determining whether”, indicating that this claim encompasses determining that the subject does not have one or two alleles of APOE e4. In such a situation, the claim does not have any instructions (the “if” condition is not met) and so the limitations of claim 74 is met when both statuses are determined but do not meet the claimed criteria regardless of any additional steps.
Therefore, claims 1, 7-16, 19-21, and 73-74 would have been obvious.
Double Patenting
Claims 1, 7-13, 16, 19-20 and 73-74 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 and 37 of copending Application No. 18/727835 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Reference claim 1 requires determining the tau burden of a patient (human subject) via tau PET where the patient is selected as a candidate for receiving AD therapy if they have SUVr values of about 1.05-1.45. This meets the instant criteria for determining the subject having low to moderate tau (see instant claim 16). Reference claim 16 includes administering AD therapy. See also reference claim 17. This therapy is donanemab (reference claim 19), which is an anti-Aß antibody. This combination meets every limitation of instant claim 1.
Regarding claim 7, the instant specification defines “treating” broadly to include embodiments such as slowing a symptom of the disease. The specification does not define any particular amount of time required to “treat”. As the reference claims the method is one of treating AD, the amount must necessarily be an effective amount for a duration sufficient to treat the disease.
Regarding claim 8, the claim is directed to results of the administration step. As the reference meets the limitations of this administration step, these results must necessarily follow.
Regarding claim 9, reference claim 10 claims analyzing amyloid by PET as well as analyzing CSF for Aß (a biomarker for Aß). It would have been obvious that these claimed methods could be used to determine a reduction of Aß deposits because they are claimed to detect Aß deposits or a biomarker for Aß.
Regarding claim 10, this would have been obvious to a person of ordinary skill in the art at the time of filing to continue a therapeutic treatment (e.g., reference claims 16 and 17) until the pathology of the disease is reduced. See MPEP 2141(II)(C): "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. The art teaches Aß deposits (plaques) in the brain are deleterious and that the Aß antibody of the method reduces these plaques. Continuing to reduce these plaques as much as possible, including 18-100%, is one such inference or creative step.
Regarding claim 11, the claim is directed to results of the administration step. As the reference meets the limitations of this administration step, these results must necessarily follow.
Regarding claim 12, this would have been obvious to a person of ordinary skill in the art at the time of filing to continue a therapeutic treatment until the pathology of the disease is reduced. See MPEP 2141(II)(C): "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. Continuing to reduce Aß plaques (imaged in reference claim 10 and determined in reference claim 14) as much as possible, including by at least 22.5 centiloids, is one such inference or creative step. Note that claim 12 does not require measurement of the plaques, only that the plaques are reduced by the claimed amount.
Regarding claim 13, reference claim 17 identifies the subject as “having” AD, which encompasses all of the recognized stages of AD (clinical AD). The subject being suspected of having AD makes obvious preclinical AD.
Regarding claim 16, the subject has about 1.05-1.45 tau-PET SUVR, which meets the limitations of less than or equal to about 1.46 as well as about 1.10-1.46 SUVR.
Regarding claim 19, using PET is discussed above.
Regarding claim 20, donanemab is an anti-N3Glu Aß antibody.
Regarding claims 73 and 74, the reference claims determining low-moderate tau burden (e.g., claim 1 reciting 1.05-1.45 SUVR) and APOE e4 alleles (claim 13). The reference claims treating those with low-moderate tau burden (e.g., claim 16 and 17). It would have been obvious to also treat those with one or two APOE e4 alleles as discovered in reference claim 13 because the reference claims are directed to making these determinations in order to treat the disease. Further, claim 13 includes the only other option—determining zero alleles—in which case reference claim 13 anticipates claim 74 because the ”if” statement has not been satisfied and the claim only has further limitations when the subject has at least one allele.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The instant specification defines “about” to be up to +/- 10% unless the context dictates otherwise. Currently, no claim contains any context which would alter the meaning of this term and so all uses of “about” are currently interpreted according to the +/- 10% limitation.
Prior art of note includes:
Shcherbinin (IDS 2/8/24 NPL citation 5). This document discloses similar information to DeMattos and ClinicalTrials above. There is no established exception under §102, though it is noted the document was published within 12 months of the instant effective filing date.
Irizarry (IDS 2/8/24 NPL citation 33) also uses tau PET to select early symptomatic subjects to treat with Aß antibodies.
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/Adam Weidner/Primary Examiner, Art Unit 1675
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