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 .
Claims 1-37, 39, 45-46, 52-58, 61, and 68-73 have been cancelled.
Election/Restrictions
Applicant’s election without traverse of the antibody comprising the HCDRs of SEQ ID NOS: 1, 41, and 81 and the LCDRs of 121, 161, and 201 (claim 38, part (i)) corresponding to the antibody comprising a heavy chain variable domain comprising SEQ ID NO: 246 and a light chain variable domain comprising SEQ ID NO: 247 (see claim 47), in the reply filed on 7/10/2026 is acknowledged.
The elected anti-Tie2 antibody corresponds to antibody clone #3 and is also referenced as aTie2.
The prior art does not disclose an anti-Tie2 antibody having an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 corresponding to SEQ ID NOS: 1, 41, 81, 121, 161, and 201, respectively, or having a heavy chain variable domain comprising SEQ ID NO: 246 and a light chain variable domain comprising SEQ ID NO: 247. Antibodies with these sequences are claimed in U.S. Patent No 12,195,542 which issued from parent application 16/953,165. The instant application is a DIV of 16/963,165 where the antibodies were restricted from the methods of treatment. See restriction requirement mailed 7/27/2022 in 16/953,165. There was no rejoinder.
Improper Markush Grouping Rejection
Claims 38 and 47 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of claims 38 and 47 are improper because the alternatives defined by the Markush groupings do not share both a single structural similarity and a common use for the following reasons: The anti-Tie2 antibodies recited in claims 38 and 47 do not belong to an art recognized class. Each antibody has a structurally different set of six CDRs responsible for binding to Tie2. There is no evidence of record that the antibodies bind to the same epitope of Tie2 or have the substantially equivalent properties. At least for example, see Figures 4 and Figures 6A-B where differences in binding and activity for some of the claimed antibodies are shown. There is no expectation from the knowledge in the art that each of the antibodies will behave in the same way. That is, they are not interchangeable or functionally equivalent.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Note that claim 38 is not limited to the particular antibodies tested in the examples but includes others with different framework regions. There is no evidence that each of the antibodies or antigen binding fragments having the sequences recited in claim 47 could be substituted one for the other. The entirety of the VH and VL sequences recited is not required in view of the “an amino acid sequence” language. Again, see Figures 4 and Figures 6A-B where differences in binding and activity for some of the claimed antibodies are shown. They are not equivalent antibodies. Example 9 discloses that distinct epitopes are bound by at least Ab#1 (see part (xxi) of claim 38, and SEQ ID NOS: 242/243 of claim 2) and Ab#3 (the elected antibody). Finally, the antibodies tested in Example 3 are not disclosed as corresponding to those that are recited in claims 38 and 47.
Claims 38 and 47 contain improper Markush groupings of alternatives. The antibodies recited differ in structure and function.
Specification
The substitute specification filed 6/10/2024 has been entered.
Drawings
The replacement drawings were received on 6/10/2024. These drawings are acceptable except for Figure 8. The replacement drawings for Figures 8A-8B (to correct the error in the 6/10/2024 drawings) were received on 8/7/2024. These drawings are acceptable.
Claim Rejections - 35 USC § 112
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 38, 40-44, 47-51, 59-60, and 62-67 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 methods of treatment as discussed below, does not reasonably provide enablement for all methods of treatment encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Independent claims 38 and 47 are directed to methods of treating a Tie2 dysregulated disease in a subject in need thereof by administering an antibody or antigen-binding fragment thereof to the subject.
Claim 41 specifies that the Tie2 dysregulated disease comprise infectious diseases, acute respiratory distress syndrome (ARDS), ischemic injuries, ocular disorders, radiation injury, cancer, systemic sclerosis, traumatic brain injury, neuroinflammation, radiation injury, wound healing, myocardial infarction, blood brain barrier compromise, cerebral cavernous malformations, Duchenne Muscular dystrophy (DMD) or Clarkson Disease. 42.
Claims 42 specifies that the Tie2 dysregulated infectious diseases comprise sepsis, dengue virus infection, tuberculosis, or influenza.
Claim 43 specifies that the Tie2 dysregulated ischemic injuries comprise diabetic nephropathy, acute kidney injury, chronic kidney disease, organ transplant, critical limb ischemia, traumatic brain injury or stroke.
Claim 44 specifies that the Tie2 dysregulated ocular disorders comprise diabetic retinopathy, diabetic macular edema (DME), proliferative diabetic retinopathy (PDR) age-related macular degeneration (AMD), retinopathy of prematurity (ROP), or glaucoma.
Paragraph [0072] of the specification discloses that a “Tie2 dysregulation disease” is any condition that would benefit from treatment with the anti-Tie2 antibody of the invention. Some examples are given but not a clear disclosure of all those conditions that would benefit from administering the anti-Tie2 antibody.
Paragraph [0077] defines “treating” as referring to clinical intervention in an attempt to alter the natural course of the individual being treated and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing recurrence of the disease or disorder, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease or disorder, decreasing the rate of disease progression, amelioration or palliation of the disease or disorder state, and remission or improved prognosis. In some embodiments, antibodies of the invention are used to delay development of a disease or disorder or to slow the progression of a disease or disorder.
As none of the claims recite any particular therapeutic effect that must occur, all aspects of treatment as defined in the specification must be enabled. Note that none of the claims requires administering a particular amount of the anti-Tie2 antibody.
First of all, there is no evidence or explanation as to why all diseases recited in claims 41-44 would be considered Tie2 dysregulated diseases. Tie2 is a receptor tyrosine kinase involved in vascular homeostasis. See at least specification paragraphs [0004 and 0282]. The claimed anti-Tie2 antibodies are disclosed as being allosteric, indirect agonists of the Tie2 receptor. They induce signal transduction through this receptor. Administration of the clone #3 antibody (the elected antibody) reduced vascular permeability induced by VEGF.
At least for example, ocular disorders such as color blindness and corneal cataracts are not associated with vascular permeability. At least for example, Duchenne Muscular dystrophy is not associated with vascular permeability. (See at least claim 41.)
At least for example, the infectious diseases of claim 42 are not associated with vascular permeability.
There is reason to doubt that many of the conditions recited in the claims are in fact Tie2 dysregulated diseases.
There is no evidence of record nor reason to believe that administration of the claimed antibodies will prevent or cure any of the recited conditions. Prevention and cure fall within the definition of “treatment” in the specification.
There is no evidence of record nor reason to believe that administration of the claimed antibodies will alleviate all symptoms or diminish all direct or indirect pathological consequences of the recited disorders. At least for example, a pathological consequence of traumatic brain injury and stroke is cognitive deficits and/or loss of motor function. There is no evidence of record nor reason to believe that administration of the claimed anti-Tie2 antibodies would regenerate damaged brain tissue and/or reverse cognitive or motor losses. At least for example, a pathological consequence of lung cancer and tuberculosis is loss of pulmonary function. There is no evidence of record nor reason to believe that administration of the claimed anti-Tie2 antibodies would regenerate lung tissue and restore pulmonary function. At least for example, a pathological consequence of glaucoma and macular degeneration is loss of vision. There is no evidence of record nor reason to believe that administration of the claimed anti-Tie2 antibodies would reverse or restore vision loss. At least for example, a pathological consequence of chronic kidney disease is damage to the kidney tissue such that dialysis or kidney transplant is required for survival. There is no evidence of record nor reason to believe that administration of the claimed anti-Tie2 antibodies would regenerate damaged kidney tissue and restore lost kidney function.
Example 5 investigated the potential physiological effects of anti-Tie2 antibodies on cellular ability to control permeability. The model allowed the further characterization of the antibodies based on their ability to enhance and/or protect physiological permeability induced by increased levels of VEGF in the microenvironment.
Example 6 investigated Tie2 activity in cells exposed to both anti-Tie2 antibodies and Ang2
Example 10 investigated oxygen-induced retinopathy in a mouse model. As shown in FIG. 8B, anti-Tie2 mAb, but not isotype control mAb or vehicle, was found to have a significant positive impact on the vaso-obliterated (i.e. avascular) area but did not appear to reduce neovascularization (Fig. 8A).
Example 11 investigated laser-induced choroidal neovascularization (CNV) in a mouse model. As shown in Figures 9A and 9B, the anti-Tie2 antibody, but not isotype control mAb, significantly inhibited choroidal neovascular lesion size following laser injury.
Note that the experimental models used in these examples are not art accepted models for conditions such as infectious diseases, radiation injuries, cancer, traumatic brain injury, wound healing, chronic kidney disease, and so forth. These results cannot be extrapolated to predict a therapeutic effect for all disorders recited in claims 41-44, particularly for all symptoms and all pathological consequences associated with these disorders. The examples in the specification do not enable prevention or cure for any disorder.
With respect to claim 40, many of the conditions recited in the claims do not involve VEGF.
With respect to claim 47, this claim recites "an amino acid sequence of SEQ ID..." The language "an amino acid sequence" is interpreted as including subsequences rather than requiring the entirety of the recited sequences. At least for example, the claim is interpreted to encompass a single amino acid from SEQ ID NO: 246 and a single amino acid from SEQ ID NO: 247. It is unclear if applicant intended to claim subsequences. Subsequences that do not contain the CDRs in their proper position within the framework regions would not have been expected to bind Tie2. The scope of claim 47 is not enabled.
The scope of claims 38, 40-44, 47-51, 59-60, and 62-67 is not enabled.
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 65-67 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 65 is confusing in reciting the “method of claim 64, wherein the antibody comprises the substitution mutation at residue N297A or N297G.” It appears that applicant intended that the “antibody comprises the substitution mutation N297A or N297G.” However, the current claim language is not clear.
Claim 66 is confusing in reciting the “method of claim 64, wherein the antibody comprises the substitution mutation at residues L234A, L235A and P329G.” It appears that applicant intended that the “antibody comprises the substitution mutations L234A, L235A and P329G.” However, the current claim language is not clear.
Claim 67 is confusing in reciting the “method of claim 64, wherein the antibody comprises the substitution mutation at residues D265A and N297G.” It appears that applicant intended that the “antibody comprises the substitution mutations D265A and N297G.” However, the current claim language is not clear.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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