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 .
Priority
The sequences recited in claims 1-4, 6, 7, 9-12, 15, and 37 are not disclosed in U.S. Provisional Application No. 63/257,373, Further, claims 2-4, 6, 7, 9-29, 33-35, 37-45, 61, and 63 all depend from claim 1.
Thus, claims 1-4, 6, 7, 9-29, 33-35, 37-45, 61, and 63 are examined with the effective filing date of October 17, 2022 and claim 50 is examined with the effective filing date of October 19, 2021, which is the filing date of U.S. Provisional Application No. 63/257,373.
Should Applicant disagree with the analysis above, he or she must point to the paragraphs or SEQ ID NOs in U.S. Provisional Application No. 63/257,373 where the sequences of claims 1-4, 6, 7, 9-12, 15, and 37 are disclosed.
Specification
The disclosure is objected to because of the following informalities:
On page 80, Examples 1-12, which describes making conditionally active proteins, is stated to be described in WO 2017/078839.
Additionally, the definition of “activity” is critical to the interpretation of the definition of conditionally active proteins and “binding activity”, yet this definition is not present in the disclosure and merely incorporated by reference to WO 2016/138071 on pages 11-12.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
Appropriate correction is required.
Claim Objections
Claim 61 is objected to because of the following informalities: claims 61 presently recites “[a] method of treatment of a neurodegenerative disease”, but would be more properly written “[a] method of treating a neurodegenerative disease”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 1-4, 6, 7, 13-29, 33-35, 37-45, 61, and 63 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.
Claim 1, from which all claims except claim 50 depend, recites a polypeptide comprising six CDRs. Claim 1 is broad and with six CDRs, four of which comprise one or two variable residues, having 64 possible combinations of CDRs. This polypeptide, although not recited, must be a single chain antibody or antibody fragment or a single polypeptide T-cell receptor, with no recited specificity, because claim 1 recites a single polypeptide comprising both the heavy and light chain CDRs. Indeed, the instant disclosure teaches anti-ApoE antibodies. Thus, the claims recite a genera of polypeptides comprising 64 species.
Additionally, claims 13-29, 33-35, and 37-45 recite a conditionally active protein, a conjugated conditionally active protein, or a diagnostic agent comprising the conditionally active protein. The instant Specification defines “conditionally active protein” as a variant or mutant of a parent protein which is more or less active at one or more aberrant condition as compared to the activity of the conditionally active protein at control or normal physiological conditions. The conditionally active protein of claim 13 requires the CDRs of claim 1. Claim 13 does not require performing a particular function of which the conditionally active protein is more or less active. However, “the term ‘activity’ as used herein refers to any function that a protein can perform, including catalyzing reactions and binding to a partner”; see paragraph 0015 of WO 2016/138071. WO 2016/138071 continues stating: For antibodies, the activity may be a binding activity (i.e., binding affinity) between an antibody and its antigen(s). For receptors or ligands, the activity may be binding affinity between a receptor and its ligand. So, the conditionally active protein of claim 13 may have more or less binding affinity. However, the instant definition does not restrict the aberrant condition or normal physiological condition. There’s no requirement, until claims 17-22, that the aberrant condition is pH and, until claims 20-22, that the aberrant condition is associated with a disease. The aberrant condition and physiological condition encompass pH, salinity or ion concentrations, temperature, glucose concentration, oxygenation status, cholesterol levels, for example. Additionally, what conditions would be considered aberrant or physiologically normal are dependent on anatomical location and disease status. For example, the pH of the stomach differs vastly from the pH of arterial blood and, thus, what would be aberrant with respect to one may be normal with respect to the other.
In contrast, Applicant has disclosed only six species having the following X1, X2, X3, X4, X5, and X6 combinations, respectively: 1. MIMMYD, 2. DIMMYP, 3. MDMMYP, 4. MIEMYP, 5. MIMEYP, and 6. MIMMDP. Additionally, Applicant has only disclosed species of conditionally active proteins wherein the aberrant condition is the pH of a brain under dementia-disease conditions and the normal physiological condition is brain pH under normal conditions.
A genus of species is not present in the instant specification or prior art that would demonstrate a structure activity relationship would be known for antibody CDR residues for the recited function of binding the protein target ApoE, as in claim 14, for example.
Antibody CDR prediction is unpredictable.
Regarding claims 1-4, 6, 7, 13-13-29, 33-35, 37-45, 61, and 63, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope; see, for example, Section “The IgG Molecule” in paragraph 1 and Figure 1 of Almagro et. al. (Frontiers in Immunology. 8:1751; Published: January 4, 2018). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori; see, for example, page 3 second and third paragraphs and page 6 ending paragraph onto page 7 of Almagro et. al.
Chiu et al. (Antibodies. 8(4): 1-80; Published: December 3, 2019) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen; see page 5, first paragraph. Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu et al. further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements; see page 6, second paragraph. Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s; see page 6, second paragraph. Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa et al. (mAbs. 9(5): 854-873; Published: April 5, 2017) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis; see page 866, last sentence left column. Hasegawa et al. taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG; see page 866, right column, first paragraph. Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis; see page 866, right column, first paragraph.
It is true that a genus may be claimed when the Specification discloses a representative number of species. Of this, AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., No. 13-1338 (Fed. Cir. 2014) opined “[o]ne factor in considering the question is how large a genus is involved and what species of the genus are described in the patent. If the genus is not large or, even if it is, the specification discloses species representing the genus throughout its scope, the requirement may be met. […] Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.” The limitation of the instant application is that there is only one species where X5 and X6 are Y and D, respectively, and only one species where X5 and X6 are D and P, respectively. Further, regarding the conditionally active protein, the claims encompass near-limitless combinations of more or less active under any conditions one may deem aberrant or physiologically normal, regardless of the type of condition, the anatomical location, or the presence or absence of a disease status. Yet, Applicant has only demonstrated the increased conditional binding affinity of six species of the genus of 64 possible CDR combinations at the pH of 6.0 compared to at the pH of a physiologically normal brain.
Thus, one of skill in the art would reasonably conclude that applicant was not in possession of the genus of CDR exchanges for the polypeptide nor the genus of conditionally active proteins at the time of filing.
Note that claims 9-12 are not included in this rejection as these claims recite the CDRs comprising fixed residues in line with the scope of the disclosure and do not recite a conditionally active protein.
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 13-29, 33-35, 37-45 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.
Claims 13-29, 33-35, 37-45 recite a conditionally active protein, a conjugated conditionally active protein, or a diagnostic agent comprising a conditionally active protein. The instant Specification defines “conditionally active protein” as a variant or mutant of a parent protein which is more or less active at one or more aberrant condition as compared to the activity of the conditionally active protein at control or normal physiological conditions. Aberrant condition in the definition is not required to be associated with a disease or even an aberrant condition within the body. And condition here is not fixed, for example to pH at a particular anatomical location or to an anatomical location and disease status. What conditions would be considered aberrant or physiologically normal are dependent on anatomical location and disease status. For example, the pH of the stomach differs vastly from the pH of arterial blood and, thus, what would be aberrant with respect to one may be normal with respect to the other. Thus, whether a protein is a conditionally active protein or not is relative to the behavior of the protein under particular, unrecited conditions.
Claim 15 recites that the conditionally active protein binds to ApoE with increased binding activity at “an aberrant condition” and later recites that the protein also has decreased binding activity in at “a normal physiological pH”. Given that the definition of conditionally active protein presents the aberrant condition and normal condition as juxtaposed and that the claim merely recites “an aberrant condition”, it is unclear if “an aberrant condition” in claim 15 is an aberrant pH. For the purpose of compact prosecution, “an aberrant condition” in claim 15 is interpreted as any condition.
Claims 23 and 24 recite a therapeutically or prophylactically effective amount of the conditionally active protein reduces ApoE-amyloid beta peptide binding and reduces C-terminal cleavage of ApoE. Claims 23 and 24 recite a product – a conditionally active protein. It is unclear what is required to meet these claims. Do claim 23 and 24 require administering a therapeutically or prophylactically effective amount? Are claims 23 and 24 merely reciting inherent properties of the conditionally active proteins? For the purpose of compact prosecution, claims 23 and 24 are interpreted as reciting inherent properties of the polypeptides of claim 1.
Claim Rejections - 35 USC § 112(d)
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 4 and 11-25 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 4 recites that polypeptide comprises a heavy chain variable region of SEQ ID NOs: 22-27 and a light chain variable region of SEQ ID NOs: 28-30. The combination of SEQ ID NOs: 22 and 28, and SEQ ID NOs: 25 and 28 comprise the variable residues of M, I, M, M, Y, and P, respectively, which are excluded from claim 1. Similarly, claims 11 and 12 include the pair of VH and VL comprising SEQ ID NOs: 25 and 28 which are excluded as recited in claim 1. Thus, claims 4, 11, and 12 further expand the scope of claim 1.
Claim 13 recites the conditionally active protein of claim 1. Conditionally active protein is defined on page 14 of the instant Specification as a variant or mutant of a parent protein which is more or less active at one or more aberrant condition as compared to the activity of the conditionally active protein at control or normal physiological conditions. Thus, claim 13 recites a function inherent to the species of proteins encompassed in claim 1 which Applicant has reduced to practice as evidenced by Tables 4, 6, and 8. Claims 14-19, and 25 recite the conditionally active protein binds ApoE and has reduced binding activity at normal physiological condition than the binding activity of the parent. This is an inherent property of the species of proteins encompassed in claim 1 which Applicant has reduced to practice as evidenced by Tables 4, 6, and 8. Claims 20-22 recite the ratio of binding activity or affinity of the conditionally active protein relative to at the pH of the dementia brain compared to normal physiological pH. These are inherent properties of the species of proteins encompassed in claim 1 which Applicant has reduced to practice as evidenced by Tables 4, 6, and 8. Claims 23 and 24 are indefinite and interpreted as reciting inherent properties of the polypeptides of claim 1.
Claims 13, 14, 16, and 20-25 recite inherent properties of the species of claim 1 which Applicant has reduced to practice and, thus, fail to limit claim 1 from which they ultimately depend.
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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 50 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step or abstract idea without significantly more. The claim recites a method for generating a conditionally active protein comprising a). mutating a parent protein to generate mutants, b). subjecting the mutants to a first assay for binding activity to ApoE at pH of a dementia brain and a second assay for binding activity at a normal physiological pH, and c). selecting the mutants which have increased binding activity to ApoE in the first assay and decreased binding activity to ApoE in the second assay. The step of “selecting” is a mental process or a task completed entirely in the mind. Thus, the step of “selecting” is an abstract idea judicial exception. This judicial exception is not integrated into a practical application because the steps of mutating and subjecting are extra-solution activities or data gathering steps which do not apply or use the exception in any way. The claim does not include additional elements that are sufficient amount to significantly more than the judicial exception because the claim only recites the additional steps of mutating and subjecting and these are well-known and conventional in the art; see Hebditch et al. (Computational and Structural Biotechnology. 18: 897-905; Published Online: April 16, 2020), Yao et al. (Science Advances. 6(43): eabd7182; Published: October 23, 2020), Spassov et al. (Proteins. 81: 704-714; Published: December 12, 2012), and Mullen et al. (Journal of Molecular Biology. 276 (4): 819-827; Published: March 6, 1998).
Thus, claim 50 is ineligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103
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.
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 50 is rejected under 35 U.S.C. 103 as being unpatentable over Short et al. (WO 2016/138071 A1; Published: September 1, 2016) in view of Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
Short et al. teaches a method comprising generating antibody mutants and assessing binding activity at a pH of 6.0 (aberrant condition) and a pH of 7.4 (normal physiological condition), wherein the conditionally active proteins demonstrated optimal binding at a pH of between 5.5 and 6.5; see Examples 6 and 7. Further, Short et al. teaches that the mutants were more active at a pH of 6.0 than the wild-type and the mutants were less active at a pH of 7.4 than the wild-type antibodies; see Example 6. Additionally, Short et al. teaches conditionally active antibodies comprise antibodies that can cross the blood-brain barrier and target antigen expressed in the brain, including ApoE; see paragraph 0415. Short et al. teaches treating neurodegenerative disease with these conditionally active proteins, including those that bind ApoE; see paragraphs 0401-0403.
Short et al. does not teach the pH of a dementia brain.
Lyros et al. teaches that participants with Alzheimer’s disease had a significantly lower pH in the white matter of the centrum semiovale compared to normal older adults; see Figure 2A.
Given that Short et al. teaches a method of generating mutants of a wild-type antibody, comparing the binding affinity of the mutant antibodies at lower pH to higher pH, and comparing the binding affinity at lower pH and higher pH to the binding affinity of the wild-type antibody, that Lyros et al. teaches that patients with Alzheimer’s disease, a type of dementia, have a lower pH in the centrum semiovale compared to normal older patients, and that Liao et al. teaches anti-ApoE antibodies as a potential therapeutic for Alzheimer’s disease (see Abstract), it would have been obvious to use the method taught by Short et al. to develop an antibody with better binding affinity to ApoE at a lower pH, more replicative of a dementia brain, compared to normal physiological conditions or the wild-type antibody.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 17 of U.S. Patent No. 10,563,194 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
Issued claims 1-11 and 17 teach a method comprising generating mutants of a wild-type antibody and screening the binding activity at an aberrant condition and a normal physiological condition to identify a conditionally active protein with decreased binding affinity at normal physiological conditions compared to aberrant conditions. The conditions recited in the issued claims impact pH.
Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22, 31, and 32 of U.S. Patent No. 11,254,932 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
Issued claims 1-22, 31, and 32 teach a method comprising generating mutants of a wild-type antibody and screening the binding activity at an aberrant condition and a normal physiological condition to identify a conditionally active protein with decreased binding affinity at normal physiological conditions compared to aberrant conditions. The conditions recited in the issued claims impact pH.
Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,472,876 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
Issued claims 1-22, 31, and 32 teach a method comprising generating mutants of a wild-type antibody and screening the binding activity at a lower pH and higher pH to identify a conditionally active protein with decreased binding affinity at high pH compared to a lower pH.
Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,110,611 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
Issued claims 1-8 teach a method comprising generating mutants of a wild-type antibody and screening the binding activity at a lower aberrant pH and higher physiologically normal pH to identify a conditionally active protein with decreased binding affinity at high pH compared to a lower pH.
Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,773,509 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
Issued claims 1-19 teach a method comprising generating mutants of a wild-type antibody and screening the binding activity at a lower pH and higher physiologically normal pH to identify a conditionally active protein which is reversibly inactivated at high pH compared to a lower pH.
Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,279,924 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
Issued claims 1-21 teach a method comprising generating mutants of a wild-type antibody and screening the binding activity at a lower aberrant pH and higher physiologically normal pH to identify a conditionally active protein which is reversibly inactivated at high pH compared to a lower pH.
The analysis below is applicable to the rejections over the claims of U.S. Patent Nos. 10,563,194; 11,254,932; 11,472,876; 12,110,611; 11,773,509; and 11,279,924.
The claims of U.S. Patent Nos. 10,563,194; 11,254,932; 11,472,876; 12,110,611; 11,773,509; and 11,279,924 do not teach comparing the binding affinity of the mutants to the wild-type antibody.
Short et al. teaches a similar method comprising generating antibody mutants and assessing binding activity at a pH of 6.0 (aberrant condition) and a pH of 7.4 (normal physiological condition), wherein the conditionally active proteins demonstrated optimal binding at a pH of between 5.5 and 6.5; see Examples 6 and 7. Further, Short et al. teaches that the mutants were more active at a pH of 6.0 than the wild-type and the mutants were less active at a pH of 7.4 than the wild-type antibodies; see Example 6. Additionally, Short et al. teaches conditionally active antibodies comprise antibodies that can cross the blood-brain barrier and target antigen expressed in the brain, including ApoE; see paragraph 0415. Short et al. teaches treating neurodegenerative disease with these conditionally active proteins, including those that bind ApoE; see paragraphs 0401-0403.
Short et al. does not teach the pH of a dementia brain.
Lyros et al. teaches that participants with Alzheimer’s disease had a significantly lower pH in the white matter of the centrum semiovale compared to normal older adults; see Figure 2A.
Given that Short et al. teaches a method similar to issued claims and further compares the binding affinity at lower pH and higher pH to the binding affinity of the wild-type antibody, that Lyros et al. teaches that patients with Alzheimer’s disease, a type of dementia, have a lower pH in the centrum semiovale compared to normal older patients, and that Liao et al. teaches anti-ApoE antibodies as a potential therapeutic for Alzheimer’s disease (see Abstract), it would have been obvious to use the method taught by the claims of U.S. Patent Nos. 10,563,194; 11,254,932; 11,472,876; 12,110,611; 11,773,509; or 11,279,924 modified to further compare the binding affinity at the conditions to that of the wild-type antibody as taught by Short et al. to develop an antibody with better binding affinity to ApoE at a lower pH, more replicative of a dementia brain, compared to normal physiological conditions or the wild-type antibody.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 50 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 18/820,633 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
This is a provisional nonstatutory double patenting rejection.
Copending claims 1-12 teach a method of generating conditionally active protein comprising evolving DNA to express DNA mutant proteins, screening mutants and selecting mutants which exhibit increased activity in an aberrant condition compared to a normal physiological condition, wherein the conditions are pH.
Claim 50 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 10, 13, 17, 19, 28-30, and 32 of copending Application No. 17/264,702 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
This is a provisional nonstatutory double patenting rejection.
Copending claims 1, 3, 5, 10, 13, 17, 19, 28-30, and 32 teach a method of generating conditionally active protein comprising evolving DNA to express DNA mutant proteins, screening mutants and selecting mutants which exhibit increased activity in an aberrant condition compared to a normal physiological condition, wherein the conditions are pH.
Claim 50 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51-67 of copending Application No. 17/820,913 in view of Short et al. (WO 2016/138071 A1; Published: September 1, 2016), Lyros et al. (Neurobiology of Aging. 87: 60-69; Published: November 22, 2019) and Liao et al. (Journal of Clinical Investigation. 128(5): 2144-2155; Published: March 30, 2018).
This is a provisional nonstatutory double patenting rejection.
Copending claims 51-67 teach a method of generating conditionally active protein comprising evolving DNA to express DNA mutant proteins, screening mutants and selecting mutants which exhibit increased activity in an aberrant condition compared to a normal physiological condition, wherein the conditions are pH separated by up to 4 pH units.
The analysis below is applicable to the rejections over the claims of copending Application Nos. 18/820,633; 17/264,702; and 17/820,913.
The claims of copending Application Nos. 18/820,633; 17/264,702; and 17/820,913 do not teach comparing the binding affinity of the mutants to the wild-type antibody.
Short et al. teaches a similar method comprising generating antibody mutants and assessing binding activity at a pH of 6.0 (aberrant condition) and a pH of 7.4 (normal physiological condition), wherein the conditionally active proteins demonstrated optimal binding at a pH of between 5.5 and 6.5; see Examples 6 and 7. Further, Short et al. teaches that the mutants were more active at a pH of 6.0 than the wild-type and the mutants were less active at a pH of 7.4 than the wild-type antibodies; see Example 6. Additionally, Short et al. teaches conditionally active antibodies comprise antibodies that can cross the blood-brain barrier and target antigen expressed in the brain, including ApoE; see paragraph 0415. Short et al. teaches treating neurodegenerative disease with these conditionally active proteins, including those that bind ApoE; see paragraphs 0401-0403.
Short et al. does not teach the pH of a dementia brain.
Lyros et al. teaches that participants with Alzheimer’s disease had a significantly lower pH in the white matter of the centrum semiovale compared to normal older adults; see Figure 2A.
Given that Short et al. teaches a method similar to issued claims and further compares the binding affinity at lower pH and higher pH to the binding affinity of the wild-type antibody, that Lyros et al. teaches that patients with Alzheimer’s disease, a type of dementia, have a lower pH in the centrum semiovale compared to normal older patients, and that Liao et al. teaches anti-ApoE antibodies as a potential therapeutic for Alzheimer’s disease (see Abstract), it would have been obvious to use the method taught by the claims of copending Application Nos. 18/820,633; 17/264,702; or 17/820,913 modified to further compare the binding affinity at the conditions to that of the wild-type antibody as taught by Short et al. to develop an antibody with better binding affinity to ApoE at a lower pH, more replicative of a dementia brain, compared to normal physiological conditions or the wild-type antibody.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Allowable Subject Matter
No claims are presently allowed.
Claims 9 and 10 are 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.
The following is a statement of reasons for the indication of allowable subject matter:
The isolated anti-ApoE antibody comprising the CDRs of SEQ ID NOs: 31, 32, 33, 34, 35, and 36, wherein the variable residues are selected from the following combinations:
X1, X2, X3, X4, X5, and X6 are M, I, M, M, Y, and D, respectively,
X1, X2, X3, X4, X5, and X6 are D, I, M, M, Y, and P, respectively,
X1, X2, X3, X4, X5, and X6 are M, D, M, M, Y, and P, respectively,
X1, X2, X3, X4, X5, and X6 are M, I, E, M, Y, and P, respectively,
X1, X2, X3, X4, X5, and X6 are M, I, M, E, Y, and P, respectively, and
X1, X2, X3, X4, X5, and X6 are M, I, M, M, D, and P, respectively;
and the method of treating a neurological disease comprising administering the forementioned isolated polypeptide are not taught by the prior art.
Holtzman et al. (WO 2012/075422 A2; Published: June 7, 2012) teaches an anti-ApoE antibody comprising SEQ ID NOs: 12 and 11 which comprise instant SEQ ID NOs: 31, 32, 33, 34, 35, and 36, wherein X1, X2, X3, X4, X5, and X6 are M, I, M, M, Y, and P, respectively. Despite the homology shared between the anti-ApoE antibody taught by Holtzman et al. and those indicated as potentially allowable above, there is no teaching in Holtzman et al. to suggest that the in variable residues may be mutated and retain the ability to bind ApoE. Indeed, the prior art as cited in the rejection under 35 U.S.C. 112(a) teach that mutations within the CDRs may result in unpredictable changes to antigen binding.
Conclusion
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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