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 .
DETAILED ACTION
Election Response
The Election filed 4/7/2026, in response to the Office Action of 1/7/2026, is acknowledged and has been entered. Applicants elected without traverse Group I (claims 1, 2, 9-13, 19 and 20), and the following species: (1) a bispecific antibody comprising an anti-human Abeta antibody. Claims 1-20 are pending. Claims 3-8 and 14-18 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 1, 2, 9-13, 19 and 20 are currently under prosecution.
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, 2, 9-13, 19 and 20 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a composition comprising a glycosylated monoclonal antibody, wherein said antibody is an anti-human Abeta antibody, a bispecific antibody comprising an anti-human Abeta antibody, or a fragment of an anti-human Abeta antibody comprising a glycosylated Fb region and capable of binding Abeta, wherein the antibody having N-glycosylation in the Fab regions) thereof, wherein relative to the total amount of glycosylated Fab in the composition, about 20% or less of Fab regions in the composition have an N-linked high mannose glycan. Dependent claim 12 recites that the monoclonal antibody is a bispecific antibody, wherein one of the binding specificities is for human A-beta and the other specificity is for the transferrin receptor.
Claim 1 identifies the antibody by function only, wherein the function is to bind to Abeta. No structure is recited.
The instant specification discloses the following: that the monoclonal antibody is human A-beta antibody, preferably Gantenerumab, which comprises the following sequences (VH domain CDR1-3: SEQ ID NO 1-3, respectively; VL domain CDR1-3 SEQ ID NO: 4-6, respectively, VH SEQ ID NO: 7 and VL SEQ ID NO: 8). The instant specification discloses that the bispecific antibody comprises Gantenerumab or a fragment thereof comprising the sequences listed above. [pg 27-28] The instant specification discloses that the bispecific antibody that comprises Gantenerumab, has an additional Fab fragment which binds to a human transferrin receptor, and that the bispecific antibody comprises the following sequences: heavy chain with amino acid sequence of SEQ ID NO: 8, a light chain with amino acid sequence of SEQ ID NO: 10, a heavy chain Fab fragment with an amino acid sequence of SEQ ID NO: 11; and a light chain with an amino acid sequence of SEQ ID NO: 12. [pg 29] Other than Gantenerumab, the instant specification does not disclose any other examples of the instantly claimed antibody. The specification fails to disclose any other structural sequence required of the instantly claimed antibody to function as claimed.
Further, claim 13 recites that the monoclonal antibody is a bispecific antibody comprising the instantly claimed sequences. Thus, claim 13 is drawn to a mix and match of heavy and light chain domains. These claims read that one would be able to mix and match the VH and VL domain SEQ ID Nos and arrive at the bispecific antibody. However, according to Applicant’s disclosure there are specific SEQ ID pairings for each antibody. The instant specification discloses that the bispecific antibody that comprises Gantenerumab, has an additional Fab fragment which binds to a human transferrin receptor, and that the bispecific antibody comprises the following sequences: heavy chain with amino acid sequence of SEQ ID NO: 8, a light chain with amino acid sequence of SEQ ID NO: 10, a heavy chain Fab fragment with an amino acid sequence of SEQ ID NO: 11; and a light chain with an amino acid sequence of SEQ ID NO: 12. [pg 29] One of ordinary skill in the art would understand that to mix and match heavy and light chains between antibodies, the HCDR1-3 and LCDR1-3 sequences must be identical (e.g., variability can only occur in non-CDR regions).
The structure activity relationship of the CDR antigen binding region that recognize human Abeta is not known and the binding epitopes cannot be predicted based on the antibody sequences. Soderberg et al (Neurotherapeutics (2023) 20:195–206) teaches and discusses three Abeta antibodies. Soderberg teaches that immunotherapy is a promising treatment for patients with Alzheimer’s disease, however, there are many challenges. Soderberg teaches that many monoclonal antibodies have entered clinical trials, however, there are varying degrees of success. Currently, there are only 4 antibodies in late-phase clinical development, and that these antibodies differ in their selectivity to different A-beta species that may have implications in both clinical efficacy and safety. [Abstract, introduction, Discussion]
By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
To provide adequate written description and evidence of possession of the claimed composition antibody genus, the instant specification can structurally describe representative antibodies, bispecific antibodies, or antigen binding fragments, that function to recognize Abeta and treating functions as claimed, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
Although Applicants may argue that it is possible to screen for antibodies that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The A-beta antigen provides no information about the structure of an antibody inhibits it.
Given the lack of representative examples to support the full scope of the claimed antibodies, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies that is required to practice the claimed invention.
Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
BREADTH OF THE CLAIM: The claim recites a composition for use in the diagnosis or treatment of a disease in an individual suspected of or suffering therefrom. There is no support for treatment or diagnosis of any disease.
PRESENCE OR ABSENCE OF EXAMPLES: The instant specification does not provide any examples the claimed composition for diagnosing or treating functions for any disease.
STATE OF THE ART: A search of relevant art discloses that targeting A-beta is a target and key protein in Alzheimer’s disease, Parkinson’s disease. The art also demonstrates that A-beta may be associated in other disease states, such as glaucoma and age-related macular degeneration, however, research is limited in these areas. (Abyadeh et al Amyloid-beta and tau protein beyond Alzheimer's disease. Neural Regen Res. 2024 Jun 1;19(6):1262-1276) However, the art does not reveal any demonstration that targeting A-beta may treat any disease as claimed.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine claimed antibody is administered to which population of subjects could predictably treat or diagnose each disease claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether the claimed antibodies treat as claimed. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
Claim 12 is 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 12 recites the limitation “the transferrin receptor”. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 9-11, 19 and 20 are rejected under 35 U.S.C. 102(a1)(a2) as being anticipated by Loetscher et al (US20090252724 A1; Published 10/8/2009).
Loetscher teaches a composition comprising a glycosylated monoclonal antibody, wherein said antibody is an anti-human Abeta antibody, a bi-specific antibody comprising an anti-human Abeta antibody, or a fragment of an anti-human Abeta antibody comprising a glycosylated Fab region and capable of binding Abeta, the antibody having N-glycosylation in the Fab region(s) thereof, wherein relative to the total amount of glycosylated Fab in the composition, about 20% or less of Fab regions in the composition have an N-linked high mannose glycan [0003-0004, 0014, 0021, 0086; Figure 14, ] Regarding Claim 2, Loetscher et al teaches the composition of claim 1. is a pharmaceutical composition. [0143, 0152-0154] Regarding claim 9, Loetscher teaches that the percentage of Fab regions having N-linked high mannose glycan is from about 0-15%. Regarding claim 10, Loetscher teaches that the high mannose glycan is one or a mixture of Man5 and Man6. [0100]
Regarding claim 11, Loetscher teaches the amino acid sequences of the instantly claimed antibody. See sequence alignments below. Loetscher teaches that the glycosylation is N-glycosylation of Asn52 of the heavy chain (instantly claimed SEQ ID NO: 9 ). [see sequence alignment below, and see at least 0052] Regarding claim 19, Loetscher teaches that the composition may be used for the diagnosis or treatment of a disease associated with amyloidogensis. [0284] Regarding claim 20, Loetscher teaches wherein relative amount of an N-linked high mannose glycan in the Fab region(s) to the total amount of glycosylated Fab in the composition is analyzed by hydrophilic-interaction chromatography-ultra high performance liquid chromatography (HILIC-UHPLC). [see example 7]
SEQUENCE ALIGNMENTS
VH CDR amino acid sequences:
RESULT 11
US-12-086-309B-26
(NOTE: this sequence has 2 duplicates in the database searched)
Sequence 26, US/12086309B
Patent No. 8906370
GENERAL INFORMATION
APPLICANT: F. Hoffmann-La Roche AG
APPLICANT: LOETSCHER, Hansruedi
TITLE OF INVENTION: ANTIBODIES AGAINST AMYLOID BETA 4 WITH GLYCOSYLATION IN THE VARIABLE REGION
FILE REFERENCE: K1314 US S3 (C018016/0219887)
CURRENT APPLICATION NUMBER: US/12/086,309B
CURRENT FILING DATE: 2011-09-20
PRIOR APPLICATION NUMBER: PCT/EP2006/011914
PRIOR FILING DATE: 2006-12-11
PRIOR APPLICATION NUMBER: EP 05 02 7090.9
PRIOR FILING DATE: 2005-12-12
NUMBER OF SEQ ID NOS: 76
SEQ ID NO 26
LENGTH: 475
TYPE: PRT
ORGANISM: artificial sequence
FEATURE:
OTHER INFORMATION: heavy chain with Fc region of ANTIBODY A and with leader sequence
Query Match 89.6%; Score 212.4; Length 475;
Best Local Similarity 48.9%;
Matches 44; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GFTFSSYAM--------------SAINASGTRTYYADSVKG------------------- 27
||||||||| ||||||||||||||||||
Db 45 GFTFSSYAMSWVRQAPGKGLEWVSAINASGTRTYYADSVKGRFTISRDNSKNTLYLQMNS 104
Qy 28 -------------GKGNTHKPYGYVRYFDV 44
|||||||||||||||||
Db 105 LRAEDTAVYYCARGKGNTHKPYGYVRYFDV 134
VL CDR amino acid sequences:
RESULT 7
US-12-086-309B-28
(NOTE: this sequence has 2 duplicates in the database searched)
Sequence 28, US/12086309B
Patent No. 8906370
GENERAL INFORMATION
APPLICANT: F. Hoffmann-La Roche AG
APPLICANT: LOETSCHER, Hansruedi
TITLE OF INVENTION: ANTIBODIES AGAINST AMYLOID BETA 4 WITH GLYCOSYLATION IN THE VARIABLE REGION
FILE REFERENCE: K1314 US S3 (C018016/0219887)
CURRENT APPLICATION NUMBER: US/12/086,309B
CURRENT FILING DATE: 2011-09-20
PRIOR APPLICATION NUMBER: PCT/EP2006/011914
PRIOR FILING DATE: 2006-12-11
PRIOR APPLICATION NUMBER: EP 05 02 7090.9
PRIOR FILING DATE: 2005-12-12
NUMBER OF SEQ ID NOS: 76
SEQ ID NO 28
LENGTH: 235
TYPE: PRT
ORGANISM: artificial sequence
FEATURE:
OTHER INFORMATION: light chain of ANTIBODY A with leader sequence
Query Match 80.6%; Score 102.3; Length 235;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RASQSVSSSYLA---------------GASSRAT-------------------------- 19
|||||||||||| |||||||
Db 44 RASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGVPARFSGSGSGTDFTLTISSLEPED 103
Qy 20 ------LQIYNMPI 27
||||||||
Db 104 FATYYCLQIYNMPI 117
SEQ ID NO: 9
RESULT 11
US-12-086-309B-26
(NOTE: this sequence has 2 duplicates in the database searched)
Sequence 26, US/12086309B
Patent No. 8906370
GENERAL INFORMATION
APPLICANT: F. Hoffmann-La Roche AG
APPLICANT: LOETSCHER, Hansruedi
TITLE OF INVENTION: ANTIBODIES AGAINST AMYLOID BETA 4 WITH GLYCOSYLATION IN THE VARIABLE REGION
FILE REFERENCE: K1314 US S3 (C018016/0219887)
CURRENT APPLICATION NUMBER: US/12/086,309B
CURRENT FILING DATE: 2011-09-20
PRIOR APPLICATION NUMBER: PCT/EP2006/011914
PRIOR FILING DATE: 2006-12-11
PRIOR APPLICATION NUMBER: EP 05 02 7090.9
PRIOR FILING DATE: 2005-12-12
NUMBER OF SEQ ID NOS: 76
SEQ ID NO 26
LENGTH: 475
TYPE: PRT
ORGANISM: artificial sequence
FEATURE:
OTHER INFORMATION: heavy chain with Fc region of ANTIBODY A and with leader sequence
Query Match 89.6%; Score 212.4; Length 475;
Best Local Similarity 48.9%;
Matches 44; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GFTFSSYAM--------------SAINASGTRTYYADSVKG------------------- 27
||||||||| ||||||||||||||||||
Db 45 GFTFSSYAMSWVRQAPGKGLEWVSAINASGTRTYYADSVKGRFTISRDNSKNTLYLQMNS 104
Qy 28 -------------GKGNTHKPYGYVRYFDV 44
|||||||||||||||||
Db 105 LRAEDTAVYYCARGKGNTHKPYGYVRYFDV 134
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 2, 9-12, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Loetscher et al (US20090252724 A1; Published 10/8/2009), in view of Duerr et al (US10941205 B2; Published 8/9/2018).
The teachings of Loetscher are recited above. However, Loetscher does not teach that limitations of claims 12 and 13, wherein the other binding specificity of the bispecific antibody is a transferrin receptor comprising the instantly claimed sequences.
Duerr teaches a bispecific antibody that binds to a human A-beta protein and the second antigen is a human transferrin receptor. [Abstract] Duerr teaches that the antibody may be altered to an extent in which the antibody is glycosylated. [col 32, lines 30-37]
It is noted that claim(s) 12 requires the bispecific antibody to bind to human A-beta and to a transferrin receptor. This limitation would have been obvious to those of ordinary skill in the art because: (1) Loetscher teaches a composition comprising a glycosylated monoclonal antibody, wherein said antibody is a bi-specific antibody comprising an anti-human Abeta antibody, (2) Loetscher teaches known methods of glycosylation of the Fab regions, and (3) Duerr teaches a bispecific antibody that binds to human A-beta and a transferrin receptor.
Conclusion
The closest prior art made of record for claim 13 is Duerr et al (US10941205 B2; Published 8/9/2018). Duerr teaches a bispecific antibody that binds to a human A beta protein and a transferrin receptor. However, the art does not teach the sequences of the SEQ ID NO: 11 and SEQ ID NO: 12, that is the heavy and light chain of the transferrin receptor portion of the bispecific antibody.
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/SARAH A ALSOMAIRY/
Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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