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
Status of the Claims
1. Claims 1-15 are the original claims filed 6/21/2023. In the Preliminary Response of 6/21/2023, Claims 3-12 and 14-15 are amended. Claims 1-15 are the pending claims.
Priority
2. USAN 18/268,840, filed 06/21/2023, is a National Stage entry of PCT/EP2021/ 086735, International Filing Date: 12/20/2021, claims foreign priority to EP 20315503.1, filed 12/22/2020.
Information Disclosure Statement
3. As of 2/27/2026, a total of one (1) IDS is filed: 6/21/2023. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
4. The disclosure is objected to because of the following informalities:
a) The use of the term MALS, BiaCore, MassHunter, PLRP-S, ASTA, Superdex, MabSelect, Tris, Triton, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) Amend the specification to correct a typographical error for FcRn (or FcGRLN). There is no clear meaning for the term “FcgRn.”
c) Amend the specification on p. 18, line 12 to correct the phrase “Example 1 shows deals with…” The meaning of the term “deals” in the context of the complete sentence is unclear.
Appropriate correction is required.
Claim Objections
5. Claims 1-3 and 6-7 are objected to because of the following informalities:
a) Amend claim 1 to reduce the verbiage in the Markush group without changing the scope:
“wherein the additional internal disulfide bond formed between cysteine residues is selected from the group consisting of according to EU numbering.”
b) Amend claim 2 to reduce the verbiage in the Markush group without changing the scope:
“wherein the additional internal disulfide bond formed between cysteine residues is selected from the group consisting of according to EU numbering.
c) Amend claim 3 to reduce the verbiage in the Markush group without changing the scope:
“wherein the additional internal disulfide bond formed between cysteine residues is selected from the group consisting of according to EU numbering.”
d) Claim 6 is unclear for the phrase “wherein the affinity to C1q and/or FcyR1, FcyR2 and/or FcyR3 is reduced at least 10-fold.” The POSA cannot ascertain whether the phrase contains a typographical omission for inclusive or alternative terms between “C1q and/or FcγR1” and “FcγR2 and/or FcγR3” or “C1q and/or FcγR1” or “FcγR2 and/or FcγR3”. An explanation is requested.
e) Amend claim 7 to correct a typographical error for FcRn (or FcGRLN). There is no clear meaning for the term “FcgRn.”
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.
Written Description
6. Claims 1-15 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 interpretation
Claim 1 is drawn to
A molecule comprising two polypeptides, wherein said polypeptides form an antibody Fc region, wherein said two polypeptides are linked by at least two covalent bonds which are located C-terminally to the portion of each polypeptide which forms the Fc region, wherein said two polypeptides are not linked by a disulfide bond located N- terminally to the portion of each polypeptide which forms the Fc region, wherein each polypeptide comprises a CH2 domain which is part of the Fc region, wherein each of these CH2 domains comprises an additional internal disulfide bond which is not present in the corresponding wild-type CH2 domain, wherein the additional internal disulfide bond is selected from the group consisting of disulfide bonds formed between cysteine residues at the following positions according to EU numbering: P238C and D265C; P238C and L328C; S267C and A327C; and V240C and I332C.
Claims 1-15 are confusing for the phrase “wherein said two polypeptides are linked by at least two covalent bonds which are located C-terminally to the portion of each polypeptide which forms the Fc region.” The phrase does not nearly describe the intended replacement of a hinge region for the paired Fc domains from the N-terminus to the C-terminus. The abstract specifically states “…the molecules of the present invention do not comprise the disulfide bridges of the antibody hinge region but are linked C-terminally by at least two covalent bonds.” Where the N-terminal hinge is altogether missing is evident from Figure 1A and 1B much less in accordance with the meaning in claim 5 where an amino acid sequence corresponding to an antibody hinge region is present at the C-terminus.
“covalent bonds”: the specification does not elaborate or provide relevant teaching on what other type of covalent bond can be applied to the overall structure of the molecule. Claim 4 provides the only support for disulfide bonds.
Claims 1-15 are confusing for the phrase “wherein said two polypeptides are not linked by a disulfide bond located N- terminally to the portion of each polypeptide which forms the Fc region.” The phrase does not nearly describe the intended replacement of a hinge region for the paired Fc domains from the N-terminus to the C-terminus. The abstract specifically states “…the molecules of the present invention do not comprise the disulfide bridges of the antibody hinge region but are linked C-terminally by at least two covalent bonds.” Where the N-terminal hinge is altogether missing is evident from Figure 1A and 1B. Claim 6 references a control antibody of the same molecule otherwise comprising an antibody hinge region located N-terminally. Explicit in the drawing and implied by the claim is that an antibody hinge is missing from the N-terminus of the Fc regions.
The phrase “additional disulfide bonds” identified by paired residues according to EU numbering for the engineered Fc domains: P238C and D265C; P238C and L328C; S267C and A327C; and V240C and I332C, are not correlated with any function but for claims 6 and 7. Claims 6 and 7 define a function as reduced (claim 6) and not reduced (claim 7) in binding affinity. Claims 6 and 7 do not define the assays used to determine the affinity much less any values for the claimed affinity. Multiple different methods exist measure affinity or KD (e.g., BiaCore, Scatchard Plot analysis, competitive ELISA) which lead to different parametric results for the same antibody. A given polypeptide may thus fall within or outside of the claimed scope depending on which assay is used, rendering the scope of the claims ambiguous.
AS regards claims 6-7, the functions/activities recited are impliedly defined as being correlated with an engineered hinge in the Fc domains on the two polypeptides, but where in claim 1, there is no per se mention of a deleted N-terminal hinge region or an addition of a C-terminal hinge.
The claims recite only minimal structural features or partial structural features for the molecule having two polypeptides comprising a modified hinge location and enumerated cysteine residues at positions in the engineered Fc domains and none of which features are specifically correlated with any function as claim is construed.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
Disclosure and regarding a representative number of structural species.
The instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. While the specification provides general descriptions of how to make polypeptides comprising engineered Fc regions, the examples are limited for the species meeting the full breath and scope of the structure much less the even more limited function required by the claims.
The specification fully discloses prototypes having no cysteine linkage in the N-terminus, additional internal disulfide bonds, and at least two covalent bonds in the C-terminus for the clones corresponding to the GLP1-Fc series:
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The POSA could reasonably conclude that written support for the structure corresponding to the phrase “wherein said two polypeptides are linked by at least two covalent bonds which are located C-terminally to the portion of each polypeptide which forms the Fc region” is for “a sequence corresponding to the amino acid sequence of an antibody hinge” (taken from claim 5).
The POSA could reasonably conclude that written support for the structure corresponding to the phrase “wherein said two polypeptides are not linked by a disulfide bond located N- terminally to the portion of each polypeptide which forms the Fc region” is for linkers that do not comprise disulfide bonds.
Disclosure and regarding a representative number of structural species that meet the limited functional requirements.
As regards claim 6, the genus of molecules are required to possess “affinity to C1q and/or FcyR1, FcyR2 and/or FcyR3 [that] is reduced at least 10-fold, compared to the same molecule comprising an antibody hinge region located N-terminally to the portion of each polypeptide which forms the Fc region.” Careful inspection of the examples, tables and figures filed for this application do not reveal any information pertinent to the inventive GLP1-Fc series of clones that are reduced in affinity by at least 10-fold for the markers C1q and/or FcyR1, FcyR2 and/or FcyR3. Those data shown in Table 3 are for a different series of clones (mab01-mab07) that do not possess the same additional internal disulfide bonds of generic claim 1. Accordingly, the subject matter of claim 6 is not substantiated by any data filed in the original application.
AS regards claim 7, the genus of molecules are required to possess “affinity to protein A and/or FcgRn [that] is not reduced, compared to the same molecule comprising an antibody hinge region located N-terminally to the portion of each polypeptide which forms the Fc region.” Table 5 data show the Kd for binding to hFcRn for the GLP1-Fc series of clones relevant to the claimed generic invention but the control antibody construct for these experiments is not well defined in the specification.
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Notably, the Kd amongst the highlighted clones is variable for those tested. Notably, GLP1-Fc06 having substitutions at P238C and D265C results in considerable loss of GLP1 activity. Thus, it is NOT clear without a defined control that the data in the specification substantiate the affinity is not reduced for FcRn binding.
In addition, insofar as experimentation performed using protein A binding in the determination of affinity, the use of protein A is for conventional purification so in this case, all of the clones retain protein A binding as shown in Table 4 and Figure 10 for the purified protein bands on SDS_PAGE gels.
Conclusion
The POSA could reasonably conclude that because the specification is insufficient in data that support Applicant being in possession of the full breadth and scope of the invention, the claims do not meet the requirements under written description.
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.
7. Claim(s) 1, 4-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (USPN 9518132 B2; issued 2016-12-13) in view of Bramhill et al (US 9156917 B2; issued 2015-10-13).
Claims 1-5 and 8-15 are prima facie obvious over Li in view of Bramhill.
As regards claims 1, 4-5 and 7, Li teaches molecules comprising two polypeptides that form an antibody Fc region, where the two polypeptides are linked by at least 2 covalent bonds located C-terminal to each of the Fc regions, where the two polypeptides are not linked by a disulfide bond N-terminal to each the Fc regions, and where each polypeptide comprises a CH2 and CH3 domain in Figure 2:
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. Li teaches the advantage of the construct for the Fc structure renders the protein with long serum half life because the antibody interaction with the neonatal receptor (FcRn) should be intact as a regular IgG (176). Li teaches deletion of CH2 in the modality which eliminates the FcRn binding property can shorten the serum half life (177). Thus Li teaches the CH2 region is important for FcRN binding and that the construct provides antibody modalities which will not activate target receptors upon binding and in the meantime offer improved profiles on product stability, safety and manufacturability.
Bramhill teaches CH2 domains with an additional disulfide bond, for example due to the substitutions V240C and I332C (whole document, especially Table 3; SEQ ID NO: 48; claim 17; Col.46, lines 24-26) and that additional disulfide bonds confer additional stability. Bramhill provides the motivation to modify CH2 domains in order to enhance stability at taught by Li stating (39) the CH2 domain template molecule retains binding to FcRn. In some embodiments, the CH2 domain template molecule comprises at least one functional FcRn binding site. In some embodiments, the CH2 domain template molecule comprises at least one functional FcRn binding site, the FcRn binding site being modified to enhance serum half life and that render claim 1 obvious.
AS regards claim 6, Li teaches at (174) Because the hinge sequence including the disulfide bonds N-terminus of the Fc structure in this novel modality is deleted, the FcγR binding of the DISCObody is greatly reduced. Therefore, the DISCObody based on this modality do not cross link cell surface receptors and activate them.
AS regards claim 7, Li teaches at (175) In one aspect, the Fc structure in one version of the DISCObody provides a convenience for protein purification using protein A or protein G chromatography.
AS regards claims 8-10, Li teaches and claims 6. The polypeptide complex of claim 1 wherein the immunoglobulin is selected from the group consisting of IgA, IgD, IgE, IgG, and IgM.
AS regards claim 9, Li teaches N-terminal CH3-hinges for the construct at Figures 3-4.
As regards claim 11, Li teaches two covalent bonds C-terminal to the CH3 on the two polypeptides (see figure herein above).
As regards claims 12 and 14, Li teaches an example of an active moiety e.g., a antigen binding moiety such as a Fab hinge fusion, attached to the hinge of both polypeptides shown in the figure herein above, or a scfv hinge fusion as sown in Figure 5A of Li.
As regards claim 13, Li teaches antigen binding moieties attached to a CH2 domain for either polypeptide of the molecule at (17) In certain embodiments, the first antigen-binding domain and/or the second binding domain further comprise a CH2 domain from the immunoglobulin and the C-terminal of the CH2 domain is covalently linked to the N-terminal of the CH3 domain.
AS regards claim 15, Li teaches at polynucleotides encoding the molecule at (166) In certain embodiments, the polypeptide complexes can be used to reduce the simultaneous binding of antigen targets to both the first and the second antigen-binding domains. In certain embodiments, conventional antibodies or antigen-binding fragments capable of binding to two antigens may be engineered into a polypeptide complex provided herein, and the simultaneous binding of the two antigens may be then determined. For example, the polynucleotides encoding a conventional antibody may be rearranged to make a first polynucleotide which encodes the CH3 domain, CH2 domain, hinge sequence, CH1 domain and VH domain sequentially from 5′ end to 3′ end, and a second polynucleotide which encodes CL domain and VL domain sequentially from 5′ end to 3′ end. The polynucleotides may be further modified to suit specific needs, for example, the CH2 domain encoding sequence may be deleted, or the hinge region may be modified to include a cysteine codon at an appropriate site. The engineered first and second polynucleotides may be expressed under suitable conditions to form the polypeptide complexes. In certain embodiments, the polypeptide complexes may reduce the simultaneous binding of antigen targets by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.
Li specifically teaches the advantages of the engineered antibody at:
(96) In certain embodiments, the polypeptide complexes have substantially reduced simultaneous binding of the first antigen-binding domain and the second antigen-binding domain to an antigen target. Such polypeptide complexes can be functional in inhibition of the antigen targets, preferably for those antigen targets that tend to be activated when brought in sufficient proximity, e.g. by simultaneous binding to the first and the second antigen-binding domains. Unwanted activation of the antigen targets caused by simultaneous binding can be undesirable and in certain circumstances even detrimental, where the elimination and/or inhibition of the targets is needed. For example, when conventional antibody is used to treat a tumor by inhibiting a receptor tyrosine kinase, the antigen-binding domains of the conventional antibody can simultaneously accommodate two receptor tyrosine kinases which are brought close enough so that they can phosphorylate each other into an activated form and induce signal transduction leading to aggravation of the tumor condition. Activation of antigen targets can also result in other side effects, for example, current anti-CD3 antibodies can activate CD3 and induce side effects such as cytokine storm, lymphopenia, redistribution and marginalization of T cells, reactivation of Epstein-Barr virus (EBV). Certain embodiments of the polypeptide complex provided herein can substantially reduce simultaneous binding of the antigen targets and hence prevent or reduce target activation, and thereby enhance the efficiency of target inhibition as well as prevent or reduce the side effects related to target activation.
(97) In certain embodiments, the polypeptide complexes further comprise one or more additional antigen-binding domains apart from the first and the second antigen-binding domains. The additional antigen-binding domains may bind to one or more antigen targets different from the existing antigen target bound by the first and the second antigen-binding domain. In certain embodiments, the one or more antigen targets can be a molecule locating nearby the existing antigen target, such that the polypeptide complexes can be specifically enriched in the neighborhood of the existing antigen target and thus improve the specificity of the action. In certain embodiments, the one or more antigen targets can involve in the same or similar condition as the existing antigen target, and the polypeptide complex can be functional in simultaneously inhibiting multiple targets and thus provide combinatorial or even synergistic effects on the condition or be effective on a broad band of related conditions, such as a broad band of tumors. In certain embodiments, the one or more additional antigen targets can be immune cell surface markers, and the existing antigen target can be a disease target, by simultaneous binding to the immune cell surface marker and the disease target, the polypeptide complex can draw the immune cell to the disease target and promote the immune response against the disease target. In certain embodiments, the one or more antigen targets can be two different markers present on a diseased cell, and the existing antigen target can be an immune cell surface marker, by simultaneous binding to the two disease markers, the polypeptide complex can specifically direct the immune cell to the target containing both disease targets and promote the immune response against the diseased cell, as a result, unwanted immune response to normal cells containing only one of the disease marker can be prevented or reduced.
The combination of Li and Bramhill provide the motivation to make and use an engineered antibody by modifying a CH2 domain that is critical to the stability of the molecule and to the extent that the FcRn binding activity is not interfered. The combination of Li and Bramhill provide the motivation advise the necessity of reducing FcgammaR binding, maintaining FcRn binding, and avoiding crosslinking by the rearranged position of the hinge region to be C-terminal to the CH2-CH3 portion of the Fc domain. Li teaches and provides a predictable and reasonable expectation of success in view of Bramhill for generating antibody modalities which will not activate target receptors upon binding and in the meantime offer improved profiles on product stability, safety and manufacturability.
Conclusion
8. No claims are allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643