DETAILED ACTION
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 the Claims
Claims 1-12 are pending. Examiner previously required a restriction (dated August 14, 2025). In response, Applicant elected, without traverse, Group I which originally encompassed claims 1, 4-8, and 12 from the claim set filed on September 28, 2022. Applicant has since provided a newly amended claim set filed on February 16, 2026 wherein claim 12 is now dependent on claim 11 which is part of invention Group II. Hence, in this office action, Examiner will only be examining claims 1 and 4-8. Accordingly, claims 2, 3, and 9-12 are withdrawn.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/CA2021/050405, filed on March 29, 2021. This application also claims the benefits of foreign priority to 63/002,449, filed on March 31, 2020.
Election/Restrictions
As a reminder, Applicant elected, without traverse, Group I which now corresponds to claims 1 and 4-8. Applicant also elected the following species without traverse:
Artemisia annua (Chinese wormwood) as the natural product,
An antibody as the inhibitor type, and
Rebastinib as the modulator of the Angiopoietin-2 mediated Tie-2 angiogenic pathway
and indicated that claims 1 and 4-8 read on the elected species.
A method of treating and/or delaying the onset of Alzheimer’s disease by inhibiting Angiopoietin-2 mediated Tie-2 angiogenic pathway comprising administering to a subject an effective amount of any of the elected species were not found in the prior art and, thus, the search was expanded.
Information Disclosure Statement
The instant application is accompanied with no IDS. Examiner would like to remind Applicant that “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section. The duty to disclose information exists with respect to each pending claim until the claim is cancelled or withdrawn from consideration, or the application becomes abandoned. Information material to the patentability of a claim that is cancelled or withdrawn from consideration need not be submitted if the information is not material to the patentability of any claim remaining under consideration in the application. There is no duty to submit information which is not material to the patentability of any existing claim. The duty to disclose all information known to be material to patentability is deemed to be satisfied if all information known to be material to patentability of any claim issued in a patent was cited by the Office or submitted to the Office in the manner prescribed by §§ 1.97(b) -(d) and 1.98. However, no patent will be granted on an application in connection with which fraud on the Office was practiced or attempted or the duty of disclosure was violated through bad faith or intentional misconduct.” See 37 C.F.R. 1.56 for more details.
Drawings
The drawings are objected to because of the following informalities:
As the figures provided in the instant application are in black and white, many figures that may have been originally depicted in color now appear as black squares which do not provide any meaningful information. See, for example, figures 3, 4, 7-9, 12-14, 16-18, and 20.
Additionally, in figures 2a and 2b, the bar graphs show what may be a white bar that blends in on the page such that the bar graph appears to have a bar missing in the plot.
Applicant’s cooperation is requested in making the figures provided in the application clearer to readers.
Specification - Disclosure
The specification is objected to because of the following informalities:
On pg. 15, line 2:
“blocking soluble soluble Aβ interacting with Tie-2” should read“blocking soluble Aβ interacting with Tie-2”
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1 and 5-7 are objected to because of the following informalities:
For clarity, claim 1 should read:
“A method of treating Alzheimer's disease in a subject by inhibiting Angiopoietin-2 mediated Tie-2 angiogenic pathway comprising administering to the subject an effective amount of an inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway.”
In claim 5:
“Acacia aulacocarpa,,” should read “Acacia aulacocarpa,”
i.e., the extra comma after “aulacocarpa” should be removed.
For clarity, claim 6 should read:
“The method of claim 1, wherein the inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway is an antibody that binds ANG-2 and/or TIE2, a non-antibody peptide that binds ANG-2, a non-antibody peptide that binds TIE2, or a small molecule inhibitor of ANG-2 or TIE2.”
For clarity, claim 7 should read:
“The method of claim 1, wherein the inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway is Trebananib, Vanucizumab, MEDI3617, Nesvacumab, Rebastinib, MGCD-265, Pexmetinib, CEP-11981, BAY-826, 3,21-dioxo-olean-18-en-oic acid, Altiratinib, 4-[4-(6-methoxy-2-naphthalenyl)-2-[4-(methylsulfinyl)phenyl]-1H-imidazol-5-yl]-pyridine, AB536, 2×CON, or L1-7.
Appropriate correction is required.
Note: Claims may need to be further amended based on the rejections explained below.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Singh, C. S. B. Mechanism Underlying Dysregulated Cerebral Vessel Growth in Alzheimer’s Disease. Ph.D. Dissertation, University of British Columbia, April 2019.https://open.library.ubc.ca/soa/cIRcle/collections/ubctheses/24/items/1.0378519
The instant disclosure was previously reported in the dissertation of Singh (i.e., one of the instant inventors) who was “responsible for experimental design, execution, and data analysis” (see “Preface” of dissertation on pg. vi). The second inventor of the instant application, Wilfred Jefferies, “supervised the project” (see “Preface”). As such, the dissertation of Singh does not qualify as prior art as the results from the dissertation were made available within the one-year grace period.
There is no prior art published before April 2019 that discloses or suggests a method of treating and/or delaying the onset of Alzheimer’s disease in a subject by inhibiting Angiopoietin-2 mediated Tie-2 angiogenic pathway comprising administering to the subject an effective amount of an inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway.
Hence, instant claims 1 and 4-8 are considered novel and nonobvious.
Note on Examiner’s interpretation of terms
According to the instant specification:
“In specific embodiments, cerebral neo-angiogenesis is inhibited by inhibiting the Angiopoietin-2 mediated Tie-2 angiogenic pathway. This pathway may be inhibited by inhibiting the Angiopoietin-2 Tie-2 binding, blocking Tie2 signalling, blocking effector molecules, blocking soluble Aβ interacting with Tie-2” (paragraph that bridges pg. 14 and 15 of instant specification).
In the description for Figure 10, it mentions: “VEGF effector moves out into the extracellular space, further facilitating Ang-2 in continuously binding to Tie-2 receptor molecules and constitutively activating endothelial cells, leading to the formation of pathogenically sprouting vessels” (pg. 7).
VEGF receptor (VEGFR) inhibitors (i.e., compounds that block the VEGF effector from binding to VEGFR) include Axitinib, Sunitinib, and DC101 (pg. 16, 2nd paragraph).
Therefore, Examiner interprets “inhibitors of Angiopoietin-2 mediated Tie-2 angiogenic pathway” to also include VEGFR inhibitors.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 and 4-8 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:
A method of treating Alzheimer's disease in a subject by inhibiting Angiopoietin-2 mediated Tie-2 angiogenic pathway comprising administering to the subject an effective amount of an inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway
wherein the inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway is any of the inhibitors listed in instant claim 7 or Axitinib, Sunitinib, or DC101
The method of (1), further comprising administration of additional therapeutic agents
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed to make and use the invention based on the content of the disclosure, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims a method of treating or delaying the onset of Alzheimer's disease or other neurological diseases in a patient having or at risk of developing Alzheimer's disease or other neurological diseases comprising administering to the subject an effective amount of an anti-angiogenic agent. In particular, the present invention provides a method of treating and/or delaying the onset of Alzheimer's disease or other neurological diseases by inhibiting Angiopoietin-2 mediated Tie-2 angiogenic pathway comprising administering to the subject an effective amount of an inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in Alzheimer’s disease research and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
State of the prior art
See “Examiner’s note on novelty and nonobviousness” section above.
The predictability or lack thereof in the art
As mentioned previously, the claimed invention (i.e., namely, a method of treating and/or delaying the onset of Alzheimer’s disease in a subject by inhibiting the Angiopoietin-2 mediated Tie-2 angiogenic pathway comprising administering to the subject an effective amount of an inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway) is considered as novel and nonobvious. As such, the prior art does not provide information or guidance that would allow a POSITA to predict which inhibitors of this pathway would be effective for treating and/or delaying the onset of Alzheimer’s disease. In particular, the prior art does not disclose a structure-activity relationship or other predictive framework that links inhibitors of the Angiopoietin-2 mediated Tie-2 pathway with therapeutic efficacy in Alzheimer’s disease models such as Tg2576 mice.
The presence or absence of working examples
The results from the working examples are as follows:
“It was also noted that Axitinib treatment showed lower expression of angiogenic marker CD105, lower amyloid load, higher expression of TJPs like ZO1 and occludin, and a more functional BBB in aged Tg2576 mice. Thus, Axitinib can alter cerebral pathology, amyloid load and other pathological indications seen in the Tg2576 mouse model of AD and show great potential as a proof of concept that with the inhibition of cerebral neo-angiogenesis cognitive decline can be treated as well as the molecular pathology seen in AD can be altered” (instant specification, pg. 40, 1st paragraph).
“This study showed that treatment with Axitinib improves cognition of the aged Tg2576 mice” (instant specification, pg. 40, 2nd paragraph, 1st sentence).
“The conclusion drawn from these results is that one-month treatment with Sunitinib can improve memory aspects like reference memory, working memory and awareness of a novel environment to promote thigmotaxis and can also prevent the further decline of spatial and associative memory in aged Tg2576 mice. One-month treatment with DC-101 also improves the awareness in a novel environment while preventing further decline of spatial and associative memory in Tg2576 mice” (instant specification, pg. 48, 2nd to last paragraph).
There are no working examples of a natural product or extract being used as an inhibitor of the angiopoietin-2 mediated Tie-2 angiogenic pathway.
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
The instant specification does not provide any working examples demonstrating that a natural product or extract inhibits the Angiopoietin-2 mediated Tie-2 angiogenic pathway and is effective for treating and/or delaying the onset of Alzheimer’s disease in a subject. Natural products encompass an extremely large and structurally diverse set of compounds while extracts are complex mixtures containing numerous structurally unrelated natural products. Although the specification identifies certain natural products or extracts that can be used in the claimed invention (such as those listed in instant claim 5), the specification does not provide experimental data demonstrating that any of these compounds possess the claimed activity. Moreover, if the identified example compounds were found to be ineffective, the specification provides no meaningful guidance for identifying alterative natural products that would be suitable inhibitors of the Angiopoietin-2 mediated Tie-2 angiogenic pathway for the claimed therapeutic purpose. The specification also does not disclose what specific constituent(s) within an extract (and how to isolate said constituent(s) from said extract), or what relative concentrations of such constituents, would be required to achieve the claimed therapeutic effect. In the absence of such guidance, a POSITA would require undue experimentation to determine which natural products or extracts possess the claimed activity.
Additionally, the specification provides experimental data involving treatment of mouse models of Alzheimer’s disease for a period of one month (see instant Example 2). However, such limited experimental data does not reasonably demonstrate that administration of inhibitors of the Angiopoietin-2 mediated Tie-2 angiogenic pathway can delay the onset of Alzheimer’s disease. Alzheimer’s disease is a chronic neurodegenerative condition that develops over extended periods of time (see “Introduction” section of Sperling, R. A. et al. Alzheimer’s & Dementia 2011, 7, 280-292.). Determining whether administration of such inhibitors actually delays Alzheimer’s disease onset would require long-term studies and further experimentation beyond what is disclosed in the specification. Thus, practicing the claimed method of delaying the onset of Alzheimer’s disease would require undue experimentation.
The breadth of the claims
The claims are broad insofar as the instant claims recite a method of treating and/or delaying the onset of Alzheimer’s disease by inhibiting Angiopoietin-2 mediated Tie-2 angiogenic pathway comprising administering to a subject an effective amount of an inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway wherein the inhibitor can be a natural product or extract, an antibody, a non-antibody peptide, or a small molecule inhibitor.
Claims 4-8, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
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 1 and 4-8 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 recites “the subject.” Claim 1 never formally introduced “a subject.” Hence, there is insufficient antecedent basis for the limitation “the subject” in claim 1.
Claim 1 further recites “an effective amount of an inhibitor…” The instant specification never defines the phrase “an effective amount” and, therefore, it is unclear what amount of inhibitor is considered as “an effective amount.” Hence, claim 1 is further rendered indefinite.
Claim 6 recites “and fragments and variants thereof…” The specification does not define the structures of these “fragments and variants thereof” and, therefore, can comprise of numerous fragments and variants with structures that can potentially vary significantly from the structure of the antibody that binds ANG-2 and/or TIE2. Thus, claim 6 is rendered indefinite.
Claim 7 recites “the modulator of the Angiopoietin-2 mediated Tie-2 angiogenic pathway…” Claim 7 is dependent on claim 1 which recites “an inhibitor of the Angiopoietin-2 mediated Tie-2 angiogenic pathway” not “the modulator.” Thus, there is insufficient antecedent basis for the limitation “the modulator…” in claim 7.
Claims 4-8, which are dependent on claim 1, are also rejected for further requiring and/or reciting the indefinite limitation of claim 1.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY H. MURRAY can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624