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 .
Drawings
Applicant is advised that the label for Figure 7B is on the top of sheet 8 of 18 while the figure itself is on the bottom of sheet 7 of 18. These should not be split over two pages. Correction is required.
Specification
The disclosure is objected to because of the following informalities:
The description of Figure 9 does not describe subparts A-D.
The description of Figure 13 does not describe subparts A-D.
Appropriate correction is required.
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 1, 3-16, and 18-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification does not adequately describe the embodiments of claim 1, part (d), that will result in an antibody that binds to ANG-2.
Claim 1, part (d), recites the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOS: 54-59, respectively. Each of these sequences contains wild-card positions where the amino acid at each position can be any amino acid as indicated in the sequence listing. Figure 25 discloses these sequences where the amino acid at the position can be any amino acid with some preferable amino acids. These preferred amino acids are not features of the sequences as presented in the sequence listing. Applicant is reminded that the sequence provided in the sequence listing controls for claims reciting SEQ ID NOS. SEQ ID NO: 54 has 4 wild-card positions. SEQ ID NO: 55 has 2 wild-card positions, SEQ ID NO: 56 has 2 wild-card positions, SEQ ID NO: 57 has 2 wild-card positions. SEQ ID NO: 58 has 2 wild-card positions. SEQ ID NO: 59 has 3 wild-card positions. The number of permutations for the set of six CDRs defining the genus of antibodies encompassed is 2015 (20 naturally occurring amino acids which can each independently be present at each of the fifteen total wild-card positions in the six CDRs).
The specification discloses four antibodies that all have the same six CDRs (81H10, 86E9, 107H7, and Hz81H1.4). Antibody Amhz81H10.4.30 has a related but unique set of six CDRs. Antibody Amhz81H10.4.49 also has a related but unique set of six CDRs. That is, the specification discloses three particular sets of six CDRs for antibodies that have ANG-2 binding. These three particular sets of six CDRs are insufficient to adequately describe all sets of six CDRs encompassed by claim 1, part (d), that will have ANG-2 binding.
Claim 1, part (d), draws a fence around a perceived genus of antibodies but the genus is not adequately described. The specification exemplifies three sets of six CDRs having the properties recited in the claims and the structural variability of claim 1, part (d), is large. No reasonable structure-function correlation has been established that is commensurate in scope. The specification does not describe representative examples to support the full scope of the claims. Those of ordinary skill in the art would have understood that changing any amino acid in an antibody CDR to another amino acid would have unpredictable results with respect to antigen binding for the resulting antibody. The specification does not disclose those amino acid substitutions in SEQ ID NOS: 54-59 that will result in ANG-2 binding commensurate in scope to the claim. Antigen binding depends upon all six CDRs. Substituting amino acids in these CDRs would result in unpredictability with respect to the binding properties of the resulting protein. The exemplified embodiments cannot be extrapolated to support all of the variable embodiments embraced by the claims. Iwahashi et al. discloses that the effect of CDR replacement or a single amino acid change on the antigen binding site structure can only be known by actual structural analysis. See at least abstract and discussion section.
Claim 1, part (d), is not adequately described.
Claims 6 and 9-19 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 as discussed below, does not reasonably provide enablement for all methods 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.
Claim 6 is directed to a methods for preparing an anti-ANG-2 antibody or antigen-binding fragment thereof. However, the host cell of claim 5 does not require that the nucleic acid of claim 4 be operably linked to or under control of any expression control sequences that would be responsible for directing expression of the antibody or antigen-binding fragment. In the case of antigen-binding fragments such as single chain Fv, the nucleic acid of claim 4 does not include any linker sequences. (See claim 30.) In the case of antigen-binding fragments such as Fv, it is unclear how this fragment will assemble in the absence of the disulfide bonds present in the full length conventional antibody. Recombinant production of the antibodies and antigen-binding fragments is not enabled by the claim as written.
Page 14 of the specification defines “treatment” as including 1) a therapeutic measure that cures, postpones, alleviates the symptoms of and/or halts the progression of a diagnosed pathological condition or a disorder; and 2) a prophylactic or preventive measure that prevents and/or postpones the development of a pathological condition or a disorder. Thus, subjects in need of treatment include individuals having already developed a disorder, individuals susceptible to a disorder, and individuals to be prevented from a disorder. By this definition, “treatment” in the absence of a specifically recited therapeutic result includes prevention.
Claim 9 is directed to a method for preventing or treating a disease or a disorder associated with an ANG2 biological activity by administering an effective amount of an antibody according to claim 1. Page 4 discloses cancer and macular degeneration as examples of associated diseases. At least for example, there is no evidence of record or reason to believe that administering any of the antibodies encompassed by claim 1 will prevent or cure all cancers. At least for example, there is no evidence of record or reason to believe that administering any of the antibodies encompassed by claim 1 will cure all cancers or cure macular degeneration (i.e. restore vision loss caused by macular degeneration).
Claim 10 is directed to a method for preventing or treating a disease accompanied with vascular leakage and/or vascular inflammation, or for modulating vascular permeability, or for reducing vascular leakage and/or ameliorating a vascular inflammatory condition, comprising administering to a subject in need thereof an anti-Ang-2 antibody or antigen-binding fragment thereof of claim 1. Claim 11 is directed to the method of claim 10, wherein the disease accompanied with vascular leakage is vascular leak syndrome, acute respiratory distress syndrome, or acute lung injury; and/or wherein the disease accompanied with vascular inflammation is a vascular infection or a pulmonary inflammation. At least for example, there is no evidence of record or reason to believe that administering any of the antibodies encompassed by claim 1 will prevent or cure acute respiratory distress disorder (ARDS) (i.e. reverse any lung tissue damage). At least for example, there is no evidence of record or reason to believe that administering any of the antibodies encompassed by claim 1 will cure or prevent any bacterial infection such as pneumococcal pneumonia (caused by Streptococcus pneumoniae) or viral infection such as SARS/COVID-19.
None of the methods is enabled for the genus of antibodies encompassed by claim 1, part (d).
The claims encompass many therapeutic effects that are not enabled by the specification. It is suggested that the claims be amended to recite the particular conditions to be treated and the specific therapeutic effects intended.
The scope of the claims 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 5, 7-12, 15-16, and 18-19 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.
Regarding claim 5, the phrase “more preferably” and the parenthesized phrase “(e.g. a 293 cell or a CHO cell)” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 7, the phrases “preferably” and “such as” and “e.g.” render the claim indefinite because it is unclear whether the limitations following each phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 8, 10, 14, 16, and 18, the phrase “preferably” renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 9, the phrase “such as ” and the parenthesized phrase “(e.g., an ocular neovascularization disease and a solid tumor)” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The phrase “associated with ” in claim 9 is a relative term which renders the claim indefinite. The phrase “associated with” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what diseases or disorders are included or excluded by this phrase.
Claim 9 is further indefinite in reciting “an effective amount” without specifying any particular therapeutic effect that must be achieved. An “effective amount” is clear with respect to “preventing” but not with respect to “treating.” The metes and bounds of the claim cannot be determined.
Regarding claim 11, the phrase “preferably” and the parenthesized phrase “(e.g., viral or bacterial pneumonia)” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 12, the phrase “such as” in multiple places renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 19, the phrases “preferably” and “such as” and “more preferably” render the claim indefinite because it is unclear whether the limitations following each phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 15 recites “said subject is at risk of developing ARDS” and “suspected of having ARDS.” The claim and specification do not define the characteristics of a subject “at risk” or “suspected” for ARDS. There are no criteria provided. The metes and bounds of the subjects included or excluded cannot be determined.
Applicant is cautioned against amending the claims to be unduly “optional” as this may render the claims indefinite and confusing as to the metes and bounds of the claims, particularly where there are multiple optional limitations and/or multiple optional limitations are recited in a chain of dependent claims. See at least MPEP 2173.05(h)(II). For example, it is noted that in the absence of the optional pharmaceutical excipient and the optional second therapeutic agent, claim 7 would not further limit the subject matter of claim 1 as it would require nothing more than the antibody or antigen-binding fragment thereof of claim 1. Claim 8 depends from claim 7 and is interpreted to mean that the second therapeutic agent is required but that the pharmaceutically acceptable excipient of claim 7 remains optional. Applicant may wish to restructure the claims with respect to the optional limitations to make them unambiguous, particularly with respect to any dependent claims.
Claim 1, parts (a)-(c), are free of the prior art and would be allowable if rewritten in independent form. The CDRs recited in claim 1, part (a), are found in each of antibodies 81H10, 86E9, 107H7, and Hz81H1.4 corresponding to claim 2, parts (iv), (v), (vi), and (i), respectively. The CDRs recited in claim 1, part (b), are found in antibody Amhz81H10.4.30 corresponding to claim 2, part (ii). The CDRs recited in claim 1, part (c), are found in antibody Amhz81H10.4.49 corresponding to claim 2, part (iii). Part (d) is not allowable for the reasons set forth above.
Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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
mpa