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 .
Claim Status
Applicant’s preliminary amendments and remarks, filed 05/24/2024, are acknowledged.
Claims 7-9, 11, 14, 15, 17, 22, 27-38, 41-47, 49, 52, 56, 58-61, 63-67, 70-102, 104-106, and 108-110 are canceled.
Claims 1, 2, 5, 6, 10, 13, 19, 21, 23-26, 39, 40, 48, 50, 51, 54, 55, 57, 62, 68, 69, 103, and 107 are amended.
Claims 1-6, 10, 12, 13, 16, 18-21, 23-26, 39, 40, 48, 50, 51, 53-55, 57, 62, 68, 69, 103, and 107 are pending.
DETAILED ACTION
Election/Restrictions
Applicant’s group election without traverse of Group I in the reply filed on 06/24/2026 is acknowledged.
Applicant’s species election without traverse of HER2 as the specific target antigen for the first moiety and mannose 3 receptor as the target for the second moiety in the reply filed on 06/24/2026 is acknowledged.
Claims 25, 26, 40, 103, and 107 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/24/2026.
As such, claims 1-6, 10, 12, 13, 16, 18-21, 23, 24, 39, 48, 50, 51, 53-55, 57, 62, and 68-69 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/24/2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
The use of the term pHrodo, which is a trade name or a mark used in commerce, has been noted in Figs. 1-3B. 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.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to because Fig. 6A recites “5C9-84.86.162-M3” whereas Fig. 6B recites “5C9-84.86.162_M3” which is inconsistent.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The disclosure is objected to because of the following informalities:
[00147]: “ZebaSpin” should read “Zeba Spin”.
[00147]: “ThermoFischer” should read “Thermo Fisher”.
[00147]: “MabSelectSuRe” should read “MabSelect Sure”.
[00149]: “biolegend” should read “BioLegend”.
[00164]: “Alexa Fluor647” should read “Alexa Fluor 647”.
[00164]: “Alexa Fluor488” should read “Alexa Fluor 488”.
[00177]: “Biorad” should read “Bio-Rad”.
[00177]: “Thermofisher” should read “ThermoFisher”.
[00179]: “1:10’000” should read “1:10,000”.
[00185] recites “showed a very led to a fast and potent depletion of a circulating antigen (Example V)”. It is unclear if something is missing or if there is a typo.
Appropriate correction is required.
The use of the term Miltenyi, Gibco, Sigma, AbbVie, R&D Systems, Zeba, Thermo Fisher, HiTrap, MabSelect Sure, MabSelect PrismA, Bio-Rad, Sephadex, GlycoWorks, RapiFluor-MS, Acquity, Unifi, pHrodo, ThermoFisher, BioLegend, Nanodrop, EasySep, Peprotech, Invitrogen, Hizentra, Alexa Fluor, Janvier Labs, Qiagen, Humira, Biotek, Biotium, and PerkinElmer, 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.
Claim Objections
Claims 5, 51, 57, and 69 are objected to because of the following informalities:
Claim 5 recites duplicate target proteins within the claim (e.g., HER2, VEGFR, ErbB-2, and CXCR4).
Claim 5 recites several acronyms and/or abbreviations which should be spelled out on first occurrence.
Claim 5: “and uPAR” should remove “and”.
Claim 5: “or GPIb/IX” should remove “or”.
Claim 5: “or misfolded light chain” should remove “or”.
Claim 51: “the glycan” should read “the N-glycan”.
Claim 51: “N-acetylglusoamine” should read “N-acetylglucosamine”.
Claim 57: a comma (,) should follow “claim 50”.
Claim 69: “heavy chain variable regions” should read “heavy chain variable region”.
Claim 69: “light chain variable regions” should read “light chain variable region”.
Appropriate correction is required.
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 5, 6, 19, 51, 53, and 54 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites “misfolded light chain and misfolded transthyretin”. It is unclear whether both of the misfolded proteins are required, or just one.
Claim 6(a) recites several receptors. It is unclear if the claim is indicating that the second moiety must bind to all of the receptors recited in subpart (a) or if only one of the receptors recited are the intended target. In particular, no conjunction such as “and” or “or” appears between the last two terms of subpart “a”.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation “a mannose 3 receptor”, and the claim also recites “any endocytic carbohydrate-binding receptor recognizing Man3GlcNAc2 structure” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 19 recites the broad recitation “at least 60%”, and the claim also recites “at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Further, claim 19 recites “of the glycans of the bifunctional binding protein” which renders the claim indefinite because it indicates more than one glycan, but claim 1 only discloses of one glycan. Thus, the number of glycans on the protein is unclear.
Claim 48 recites the limitation "the bifunctional molecule" in line 3. There is insufficient antecedent basis for this limitation in the claim.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 53 recites the broad recitation “at least 50%”, and the claim also recites “at least 60%, at least 70%, at least 80%, at least 90% or 99%” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 54 recites “N-X-S/T, N-X-C motifs”. It is unclear if the slash is being used to indicate alternates (i.e., S or T), or to indicate a substitution from S to T.
Further, it is unclear whether there should be a conjunction (e.g., “or”) between “N-X-S/T” and “N-X-C motifs”.
Lastly, it is unclear whether “X” in the motif is the same amino acid residue of claim 50, or if X is a completely different amino acid residue.
Claim Rejections - 35 USC § 112(a) Written Description
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 1-6, 10, 12, 13, 16, 18-21, 23, 24, 39, 48, 50, 51, 53-55, 57, 62, 68, and 69 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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, sufficient to show the Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a bifunctional binding protein comprising a first moiety that specifically binds to a target protein and a second moiety comprising a glycan comprising the structure:
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wherein the square represents an N-acetylglucosamine residue and the hexagon represents a mannose residue, and wherein X represents an amino acid residue of the bifunctional binding protein.
Claim 2 is drawn to the bifunctional binding protein of claim 1, wherein the glycan further comprises a fucose residue at the N-acetylglucosamine that is directly attached to X.
Claim 3 is drawn to the bifunctional binding protein of claim 1, wherein X is an asparagine residue in the bifunctional binding protein.
Claim 4 is drawn to the bifunctional binding protein of claim 1, wherein the glycan consists of the structure of claim 1.
Claim 5 is drawn to the bifunctional binding protein of claim 1, wherein the target protein is HER2, EGFR, HER3, VEGFR, CD20, CD 19, CD22, αvβ3 integrin, CEA, CXCR4, MUC1, LCAM1, EphA2, PD-1, PD-L1, TIGIT, TIM3, CTLA4, VISTA, Notch receptors, EGF, c-MET, Frizzled receptors, Wnt, LRP5/6, CD38, CD73, TGF-β, Bombesin R, CAIX, CD13, CD44, v6, CXCR4, ErbB-2, Her2, Emmprin, Endoglin, EpCAM, EphA2, FAP-α, Folate R, GRP78, IGF-1R, Matriptase, Mesothelin, sMET/HGFR, MT1-MMP, MT6-MMP, Muc-1, PSCA, PSMA, Tn antigen, and uPAR, TSHRα, AChR-α1, noncollagen domain 1 of the α3 chain of type IV collagen (α3NCi), ADAMTSi3, Desmoglein-1/3, or GPIb/IX, GPIIb/IIIa, GPIa/IIa, NMDA receptor, glutamic acid decarboxylase (GAD), amphiphysin and gangliosides GM1, GD3, GQ1B, MOG, SIRPa, CCR2, CSF-1R, LILRBI, LILRB2, VEGF-R, CXCR4, CCL2, CXCL12, CSF-1, CD47, or misfolded light chain and misfolded transthyretin.
Claim 6 is drawn to the bifunctional binding protein of claim 1, wherein the second moiety specifically binds to: (a) a mannose 3 receptor, a Cluster of Differentiation 206 (CD206) receptor, a DC-SIGN (Cluster of Differentiation 209 or CD209) receptor, a C-Type Lectin Domain Family 4 Member G (LSECTin) receptor, a macrophage inducible Ca2+-dependent lectin receptor (Mincle); or (b) any endocytic carbohydrate-binding receptor recognizing Man3GlcNAc2 structure.
Claim 10 is drawn to the bifunctional binding protein of claim 1, wherein the first moiety comprises: (a) a heavy chain variable region or a light chain variable region; or (b) a Fab region of a monoclonal antibody.
Claim 12 is drawn to the bifunctional binding protein of claim 1, wherein the bifunctional binding protein is an antibody.
Claim 13 is drawn to the bifunctional binding protein of claim 12, wherein the antibody is (a)a monoclonal or polyclonal antibody; (b) recombinant; or (c) humanized, chimeric or fully human.
Claim 16 is drawn to the bifunctional binding protein of claim 12, wherein the antibody has a glycan to protein ratio of 2 to 1, 4 to 1, 6 to 1, 8 to 1, or 10 to 1.
Claim 18 is drawn to the bifunctional binding protein of claim 1, wherein the bifunctional binding protein is an autoantigen.
Claim 19 is drawn to the bifunctional binding protein of claim 1, wherein at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% of the glycans of the bifunctional binding protein have the structure of the glycan of claim 1.
Claim 20 is drawn to the bifunctional binding protein of claim 1, wherein the target protein is a cell surface molecule or a non-cell surface molecule.
Claim 21 is drawn to the bifunctional binding protein of claim 20, wherein the cell surface molecule is a receptor or the non-cell surface molecule is an extracellular protein.
Claim 23 is drawn to the bifunctional binding protein of claim 21, wherein the extracellular protein is an autoantibody, a hormone, a cytokine, a chemokine, a blood protein, or a central nervous system (CNS) protein.
Claim 24 is drawn to the bifunctional binding protein of claim 20, wherein the target protein is capable of being bound by the first moiety.
Claim 39 is drawn to a pharmaceutical composition comprising the bifunctional binding protein of claim 1 and a pharmaceutically acceptable carrier.
Claim 48 is drawn to a kit comprising the bifunctional binding protein of claim 1 and instructions for administering the bifunctional molecule to an individual in need thereof.
Claim 50 is drawn to a bifunctional binding protein, wherein the bifunctional binding protein (i) specifically binds to a target protein and (ii) comprises an N-glycan of the structure:
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wherein the square represents an N-acetylglucosamine residue and the hexagon represents a mannose residue, and wherein X represents an amino acid residue of the bifunctional binding protein, wherein the N-glycan is linked to the bifunctional binding protein at 1, 2, 3, 4 or 5 N-glycosylation sites.
Claim 51 is drawn to the bifunctional binding protein of claim 50, wherein the glycan further comprises a fucose residue at the N-acetylglucosamine that is directly attached to X and/or X is an asparagine residue in the bifunctional binding protein.
Claim 53 is drawn to a population of bifunctional binding proteins according to claim 50, wherein for at least one of the N-glycosylation sites at a specified amino acid position of the bifunctional binding protein, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 99% of N- glycosylation sites in the population are glycosylated with the N-glycan specified in claim 50.
Claim 54 is drawn to the bifunctional binding protein of claim 50, wherein the N-glycosylation site comprises one or more asparagine residues, wherein the asparagine residues are within a canonical consensus sequence N-X-S/T, N-X-C motifs, and non-canonical consensus motifs.
Claim 55 is drawn to the bifunctional binding protein of claim 50, wherein the N-glycosylation site(s) is introduced into the bifunctional protein by recombinant engineering.
Claim 57 is drawn to the bifunctional binding protein of claim 50, wherein the glycan consists of the structure of claim 50.
Claim 62 is drawn to the bifunctional binding protein of claim 50, wherein the bifunctional binding protein is an antibody.
Claim 68 is drawn to the bifunctional binding protein of claim 62, wherein the antibody comprises an N-glycosylation site in the Fc domain of the antibody and wherein the N-glycan is linked to the N-glycosylation site in the Fc domain.
Claim 69 is drawn to the bifunctional binding protein of claim 62, wherein the antibody comprises an N-glycosylation site in the heavy chain variable regions and/or light chain variable regions of the antibody and wherein the N-glycan is linked to the N-glycosylation site in the heavy chain variable regions and/or light chain variable regions.
The specification discloses of Man3 glycosylated antibody leads to efficient internalization and lysosomal compartment targeting (see Example 1). Table 1 shows the main N-glycan structure displayed by the antibodies used. Fig. 1 shows that Man3 adalimumab (A-M) was significantly more internalized than adalimumab variants displaying different N-glycans. This indicates that Man3 glycan displayed by an antibody leads to internalization and targeting of the internalized antibody to lysosomal degradation [00150].
Example 2 discloses Man3 glycosylated Fab antibody leads to efficient internalization and lysosomal targeting on human macrophages. Table 2 shows antibodies used in the experiment along with their main N-glycan structure on Fc or Fab parts. The A8486-M3 variant, displaying M3 glycan on the Fab portion, were internalized by macrophages at a high level for all donors; internalization of A8486-M3 was 17 to 39-fold higher than Humira baseline whereas the A8486-A2G2S2 variant, which had 70% of sialic acid terminated N glycans on the Fab portion, was also internalized 6 fold more efficient [00160]. These results indicate that M3 glycans displayed on the Fab portion of an antibody lead to potent internalization and targeting to the lysosomal pathway by human macrophages and Man3-mediated lysosomal targeting was more potent than sialic acid-mediated lysosomal targeting [00161].
Example 3 discloses of Man3 glycosylated Fab antibody leads to efficient internalization and lysosomal targeting in human dendritic cells. The A-M3 variant showed higher internalization than Humira or Mabthera although clearly inferior to the A-8486-M3 variant [00167]. Further, the data also show that select positioning of Man3 glycans can lead to particularly efficient internalization – Man3 glycans displayed on Fab fragment led to much more potent internalization than Man3 glycans on Fc fragment (on canonical N297) [00168].
Example 4 discloses that there is a trend for correlation between the load of M3 glycan displayed by antibodies and potency of internalization as the A-84-M3, with a single engineered glycosite per Fab, showed the lowest internalization while 5C9-84.86.162-M3 with 3 engineered glycosite per Fab, showed the highest internalization [00173]. This data and the data from Example 2 indicates that variation of the potency occurs from donor to donor [00173]. Further, Fig. 6 and Table 4 indicate that internalization of M3 antibodies by M2 macrophages is mediated by the mannose receptor (CD206) [00173].
Example 5 discloses of Man3 glycosylated Fab antibodies lead to potent in vivo depletion of a blood circulating antigen. All glycoengineered antibodies conserved high binding to the antigen, “HCA202” [00175]. Treatment with A-M3 and A-8486-A2G2S2 led to increased HCA levels as compared to PBS treatment whereas injection of A-84-M3 and A-8486-M3, displaying exposed Man3 glycans, led to complete depletion of HCA202 as compared to non-depleting antibodies and PBS already at 1 hour [00180]. This data highlights that antibodies displaying M3 glycans on their Fab fragment have a strikingly high potency to eliminate a circulating antigen from blood circulation in a very short time whereas M3 glycan displayed in the Fc fragment does not lead to active depletion [00182].
Example 6 discloses of Man3 glycosylated Fab antibody targeted to the liver in vivo. At 6-hour timepoint, only 6% of injected dose of H-A2F was present in the liver while it was detected in all other organs which is consistent with normal human IgG and characteristics of an antibody that is broadly distributed and still mainly present in the blood [00185]. A-8486-M3 antibody showed a rapid and preferential distribution to the liver area (Fig. 8); at 6 hour timepoint 19% of the injected dose of A-8486-M3 was present in the liver (Table 7). A-8486-M3 antibody was absent from thyroid, lungs, heart and kidneys and detectable only in the spleen which is characteristic of an antibody that is not present in the blood [00185].
However, the specification fails to disclose that Applicant was in possession of the large genus of bifunctional binding proteins as claimed. Specifically, the specification fails to disclose that Applicant was in possession of first moieties that bind to a large genus of target proteins. Further, the specification fails to disclose that Applicant was in possession of the claimed glycan where it attaches to any amino acid residue of the bifunctional binding protein excluding canonical N297 on the Fc region. The specification fails to disclose of the claimed bifunctional binding protein wherein the antibody has a glycan to protein ratio of 6 to 1, 8 to 1, or 10 to 1. Additionally, the specification fails to disclose that Applicant was in possession of bifunctional binding proteins wherein at least 60% of the glycans have the structure of claim 1.
Although the specification discloses A-M3, A-84-M3, and A-8486-M3, the claims are not limited to these proteins, and are inclusive of any binding protein comprising a first moiety that binds to any target protein and a second moiety comprising a glycan comprising the claimed structure. This indicates that there are hundreds, if not thousands, of possible binding proteins encompassed by the claims. Thus, the claims encompass a vast genus of binding proteins that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of binding proteins because, inter alia, the specification does not disclose a correlation between the necessary structure of the binding proteins and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecules function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/therapeutic agents and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of binding proteins. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the first moiety to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of binding proteins, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous binding proteins had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of binding proteins claimed only by a partial structure and functional characteristic(s). Thus the binding proteins described by the instant claims encompasses an overly broad genus, the structure of the first moiety, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of binding proteins by the functions of the first moiety that specifically binds to a target protein. Additionally, the claims attempt to define the genus of glycans by the location of where it attaches. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless of whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed binding proteins, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed first moiety that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies and therapeutic agents that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies/therapeutic agents or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular, higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges, it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed binding proteins could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
Regarding the first moiety that are small molecules of a particular protein target, the prediction of binding to a target, much less the inhibitory activity, is highly unpredictable. According to Guido et al. (Curr Med Chem. 2008;15(1):37-46), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may bind any particular target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al. teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al. (J. Med. Chem., 2014, 57 (12), pp 5023–5038), even when guided by structural data, developing selective structure-activity relationships has been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein, especially a particular protein family member, or treat disease.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an adequate written description 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 (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all binding proteins.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed binding proteins. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of binding proteins as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 102
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 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.
Dickey
Claims 1-6, 10, 12, 13, 19-21, 23, 24, 39, 50, 51, 53, 55, 57, 62, and 68 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dickey et al (US 2009/0060921 A1; publication date: 03/05/2009).
Dickey et al is drawn to a glycan-optimized monoclonal antibodies that specifically bind CD20 antigen and which have improved effector function (see Abstract). Example 9 describes the production of anti-CD20 and anti-HER2 monoclonal antibodies rituximab and Herceptin having increased ADCC. Fig. 59 shows the glycosylation patterns of the CHO-expressed anti-CD20 antibody, comprising GlcNAc2Man3GlcNAc2 (G0), i.e. which comprise the structure disclosed in present independent claims 1 and 50. Dickey et al disclose of anti-CD20 antibody compositions comprising at least 90% represented by the G0 glycoform (see claims 1-3). Moreover, Example 10 discloses the production of a glycan-optimized rituximab expressed in the clonal aquatic plant Lemna (LEXOpt expression system). The GO glycan species is attached to Asn297 (see [0038]). LEXOpt rituximab has been demonstrated to have the following characteristics: homogeneous GO glycans, antigen binding and apoptotic activity similar to Rituxan, 20 to 200-fold higher ADCC activity than Rituxan, 10-fold lower CDC activity than Rituxan and comparable or better B-cell depletion in whole blood (see [0280]). Dickey et al also disclose that the GO N-glycan can further comprise a fucose residue in which 1-position of the fucose is bound to 6-position of the N-acetylglucosamine in the reducing end through a bond (see [0041] and Fig. 29A). Dickey et al disclose that the glycol-protein can be formulated into a pharmaceutical composition with a pharmaceutically acceptable carrier (see claims 7 and 11; [0289] and [0306]).
As such, the teachings of Dickey et al anticipate the present invention.
Strome
Claims 1-6, 10, 12, 13, 19-21, 23, 24, 50, 51, 55, 57, 62, and 68 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Strome et al (US 2010/0173323 A1; publication date: 07/08/2010).
Strome et al is drawn to methods of generating a glycosylation-engineered antibody and using the glycosylation-engineered antibody for treating a patient, particularly a cancer patient or a patient with an immune disease or disorder (see Abstract). Specifically, Strome et al disclose of antibodies comprising N-glycans described in Figures 2 and 5, wherein N-glycan (87) shares the same structure as the glycan recited in the present claims. Strome et al disclose that the N-glycan is attached to Asn297 of the antibody (see Figure 2; Examples 4, 7, and 8) and is recombinantly produced (see [0075]). Strome et al disclose that the antibody can be monoclonal (see [0042] and [0076]) or chimeric (see Examples 7-9) that can bind to its target such as CD20 and EGFR (see [0042] and [0109]). Strome et al disclose that the N-glycan can also comprise a fucose at position N297 of the antibody (see [0068], [0075] and [0094]).
As such, the teachings of Strome et al anticipate the present invention.
Mally
Claims 1-6, 10, 12, 13, 19-21, 23, 24, 39, 48, 50, 51, 53-55, 57, 62, 68, and 69 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Mally et al (WO 2019/234021 A1; publication date: 12/12/2019). The applied reference has a common joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Mally et al disclose of methods for production and the resulting product of a monoclonal antibody with specific glycosylation profile that results in improved efficacy (see Abstract). Mally et al disclose that the antibody can be against a human protein and can be a full-length antibody, a Fab, a F(ab’)2, an scFv, or a sdAb (see [0034]). Mally et al disclose that the antibody have at least 90% to 100% of the N-linked glycosylation consensus sequences of the antibody carry an oligosaccharide that comprises the same glycan structure of instant claims 1 and 50 (see [0037]). Mally et al disclose that this oligosaccharide is the highest relative N-glycan of adalimumab (see Fig. 12B). Mally et al disclose that the oligosaccharide is linked to the asparagine of the antibody (see [0039]). Further, Mally et al disclose that the oligosaccharide can also comprise a fucose residue at the N-acetylglucosamine that is directly attached to the antibody at the Fc domain (see Fig. 2). Also, Mally et al disclose that the oligosaccharide can be linked to the heavy chain of the antibody (see [00161]). Mally et al also disclose of antibodies that target CD20 (see Example 8.27; Table 8). Mally et al disclose of pharmaceutical compositions comprising the glycosylated antibody and a pharmaceutically acceptable carrier (see [00302]). Mally et al disclose of a kit comprising the glycosylated antibody and instructions for administration (see [00308]). Mally et al disclose of a population of glycosylated antibodies wherein one or more of the antibodies comprise one or more of oligosaccharides comprising the structure of instant claim 50 and wherein at least 50% of the N-glycosylation sites carry the same oligosaccharide (see claims 20 and 21). Mally et al disclose that the N-glycosylation site comprise Asn-X-Ser/Thr (N-X-S/T) where X is any amino acid except proline (see [0061], [00145], and [00267]).
As such, the teachings of Mally et al anticipate the present invention.
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.
18/283,731
Claims 1-6, 10, 12, 13, 16, 18-21, 23, 24, 39, 48, 50, 51, 53-55, 57, 62, 68, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5-8, 12-14, 16, 20, 22, 26, 32, 34, 35, 41, 44, 46, 49, 56, 75, 76, and 84 of copending Application No. 18/283,731 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘731 application is drawn to a glycoengineered bifunctional binding protein comprising a first moiety that specifically binds to a target protein associated with a disease and at least one second moiety that binds specifically to an endocytic carbohydrate-binding protein or receptor, wherein the at least one second moiety comprises a glycan structure (see claim 1). The ‘731 application is drawn to the glycoengineered bifunctional binding protein of claim 1, wherein the at least one second moiety comprises a glycan comprising terminal GlcNAc (see claims 2, 5-8, 12, and 16). The ‘731 application is drawn to the glycoengineered bifunctional binding protein of claim 1, wherein the at least one N-glycan is linked to the bifunctional binding protein at 1, 2, 3, 4, or 5 N-glycosylation sites (see claims 8 and 12). The ’731 application is drawn to the glycoengineered bifunctional binding protein wherein a GlcNAc residue of the N-glycan is fucosylated (see claim 14). The ‘731 application is drawn to the glycoengineered bifunctional binding protein, wherein the amino acid residue is Asn (asparagine) (see claim 20). The ‘731 application is drawn to the glycoengineered bifunctional binding protein, wherein the bifunctional protein is an antibody or fragment thereof and comprises (a) a heavy chain variable region; (b) a light chain variable region; or (c) a Fab fragment (see claim 26). The ‘731 application is drawn to the glycoengineered bifunctional binding protein, wherein the antibody or fragment thereof has a glycan to protein ratio of at least 2 to 1, at least 4 to 1, at least 6 to 1, at least 8 to 1, or at least 10 to 1 (see claim 32). The ‘731 application is drawn to the glycoengineered bifunctional binding protein, wherein the glycoengineered bifunctional binding protein binds to an autoantibody and comprises an autoantigen or immunogenic fragment thereof (see claim 34). The ‘731 application is drawn to a population of the glycoengineered bifunctional binding protein of claim 1, wherein at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% of the glycans at a given glycosite are the same (see claim 35). The ‘731 application is drawn to the glycoengineered bifunctional binding protein, wherein the target protein is HER2, EGFR, HER3, VEGFR, CD20, CD 19, CD22, αvβ3 integrin, CEA, CXCR4, MUC1, LCAM1, EphA2, PD-1, PD-L1, TIGIT, TIM3, CTLA4, VISTA, Notch receptors, EGF, c-MET, Frizzled receptors, Wnt, LRP5/6, CD38, CD73, TGF-β, Bombesin R, CAIX, CD13, CD44, v6, CXCR4, ErbB-2, Her2, Emmprin, Endoglin, EpCAM, EphA2, FAP-α, Folate R, GRP78, IGF-1R, Matriptase, Mesothelin, sMET/HGFR, MT1-MMP, MT6-MMP, Muc-1, PSCA, PSMA, Tn antigen, and uPAR, TSHRα, AChR-α1, noncollagen domain 1 of the α3 chain of type IV collagen (α3NCi), ADAMTSi3, Desmoglein-1/3, or GPIb/IX, GPIIb/IIIa, GPIa/IIa, NMDA receptor, glutamic acid decarboxylase (GAD), amphiphysin and gangliosides GM1, GD3, GQ1B, MOG, SIRPa, CCR2, CSF-1R, LILRBI, LILRB2, VEGF-R, CXCR4, CCL2, CXCL12, CSF-1, CD47, or misfolded light chain and misfolded transthyretin (see claim 44). The ‘731 application is drawn to the glycoengineered bifunctional binding protein, wherein the carbohydrate-binding protein or receptor is DC-SIGN, L-SIGN, LSECTin, asialoglycoprotein receptor (ASGPR), mannose-6-phosphate receptor, mincle, dectin-1, dectin-2, langerin, cation-independent mannose 6-phosphate receptor (CI-MPR), macrophage mannose receptor 2, BDCA-2, MGL, MDL, MICL, CLEC2, DNGR1, or CLEC12B (see claim 46). The ‘731 application is drawn to a pharmaceutical composition comprising the glycoengineered bifunctional binding protein of claim 1 and a pharmaceutically acceptable carrier (see claim 75). The ‘731 application is drawn to a kit comprising the glycoengineered bifunctional binding protein of claim 1 and instructions for administering the glycoengineered bifunctional protein to an individual in need thereof (see claim 84).
The difference between the present invention and the ‘731 application is that the ‘731 application also comprise claims drawn to methods of using the claimed product. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. As such, the ‘731 application anticipates the present invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
19/116,229
Claims 1-3, 5, 6, 10, 12, 13, 16, 18-21, 23, 24, 39, 48, 50, 51, 53, 55, 62, 68, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-107 of copending Application No. 19/116,229 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘229 application is drawn to a glycoengineered bifunctional degrader, wherein the bifunctional degrader (i) specifically binds to a target protein and (ii) comprises an N-glycan of the structure:
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linked to the bifunctional degrader at one or more N-glycosylation sites, wherein the black square represents an N-acetyl galactosamine (GalNAc), the white square represents an N-acetylglucosamine (GlcNAc) residue and the black circle represents a mannose (Man) residue, and wherein X represents an amino acid residue of the bifunctional degrader (see claim 1). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the target-specific binding location is a variable region of an antibody or antigen-binding fragment (Fab), or an ectodomain of an Fc-fusion protein (see claim 12). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the amino acid residue is Asn (see claim 18). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the N-glycosylation site comprises a consensus sequence of N-S-S/T or N-X-C, wherein X is any amino acid except proline (see claim 19). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the glycoengineered bifunctional degrader is an antibody including monoclonal, polyclonal, recombinant, humanized, chimeric, or fully human (see claims 20-25). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the antibody has a glycan to protein ratio of 2 to 1, 4 to 1, 6 to 1, 8 to 1, or 10 to 1 (see claim 26). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the N-glycan is linked to an N-glycosylation site of the heavy chain or light chain of the antibody or fragment thereof (see claims 27 and 28). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the glycoengineered bifunctional degrader binds to an autoantibody and comprises an autoantigen or immunogenic fragment thereof (see claim 43). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the target protein is a cell surface molecule or a non-cell surface molecule (see claims 45-48). The ‘229 application is drawn to the glycoengineered bifunctional degrader, wherein the target protein associated with disease comprises HER2, EGFR, HER3, VEGFR, CD20, CD 19, CD22, αvβ3 integrin, CEA, CXCR4, MUC1, LCAM1, EphA2, PD-1, PD-L1, TIGIT, TIM3, CTLA4, VISTA, Notch receptors, EGF, c-MET, Frizzled receptors, Wnt, LRP5/6, CD38, CD73, TGF-β, Bombesin R, CAIX, CD13, CD44, v6, CXCR4, ErbB-2, Her2, Emmprin, Endoglin, EpCAM, EphA2, FAP-α, Folate R, GRP78, IGF-1R, Matriptase, Mesothelin, sMET/HGFR, MT1-MMP, MT6-MMP, Muc-1, PSCA, PSMA, Tn antigen, and uPAR, TSHRα, AChR-α1, noncollagen domain 1 of the α3 chain of type IV collagen (α3NCi), ADAMTSi3, Desmoglein-1/3, or GPIb/IX, GPIIb/IIIa, GPIa/IIa, NMDA receptor, glutamic acid decarboxylase (GAD), amphiphysin and gangliosides GM1, GD3, GQ1B, MOG, SIRPa, CCR2, CSF-1R, LILRBI, LILRB2, VEGF-R, CXCR4, CCL2, CXCL12, CSF-1, CD47, or misfolded light chain and misfolded transthyretin (see claim 52). The ‘229 application is drawn to a composition comprising a population of bifunctional degraders, wherein the population of bifunctional degraders has an N-glycan profile that is at least 30% homogeneous at one more of the N-glycosylation site(s) (see claims 56-65). As such, the ‘229 application anticipates the present invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
19/476,978
Claims 1-3, 5, 6, 10, 12, 13, 16, 18-21, 23, 24, 39, 48, 50, 51, 53, 55, 62, 68, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 11-15, 17, 18, 21-24, 26-28, 30, 31, 33, 34, 36, 37, 40, 41, and 43-59 of copending Application No. 19/476,978 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘978 application is drawn to a multi-functional molecule, comprising (a) a first moiety that specifically binds to an endocytic receptor; and (b) a second moiety that specifically binds to a target at a first pH (see claim 1). The ‘978 application is drawn to the multi-functional molecule, wherein the first moiety comprises one or more peptides that specifically binds to an endocytic receptor, wherein the endocytic receptor is chosen from a mannose 3 receptor, a Cluster of Differentiation 206 (CD206) receptor, a DC-SIGN (Cluster of Differentiation 209 or CD209) receptor, a C-Type Lectin Domain Family 4 Member G (LSECTin) receptor, a macrophage inducible Ca2+-dependent lectin receptor (Mincle) (see claim 15). The ‘978 application is drawn to the multi-functional molecule, wherein the first moiety comprises an antibody agent, optionally wherein the antibody agent comprises a full antibody, a Fab fragment, an scFv, a nanobody, a duobody, or a single domain antibody (see claim 17). The ‘978 application is drawn to the multi-functional molecule, wherein the glycan comprises a terminal GlcNAc (see claim 21). The ‘978 application is drawn to the multi-functional molecule, wherein the one or more glycans is an N-glycan, optionally wherein the N-glycan is linked to the second moiety and/or third moiety at 1, 2, 3, 4, or 5 N-glycosylation sites (see claim 22). The ‘978 application is drawn to the multi-functional molecule, wherein the N-glycan has a structure of:
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wherein the black square represents an N-acetyl galactosamine (GalNAc), the white square represents an N-acetylglucosamine (GlcNAc) residue and the black circle represents a mannose (Man) residue, and wherein X represents an amino acid residue of the second moiety or third moiety (see claim 26). The ‘978 application is drawn to a composition comprising a population of multi-functional molecules, wherein the population of multi-functional molecules has an N-glycan profile that is at least 30% homogeneous at one or more of the N-glycosylation site(s) (see claim 40). The ‘978 application is drawn to the composition, wherein the composition is a pharmaceutical composition, optionally wherein the pharmaceutical composition comprises one or more excipients (see claim 41).
The difference between the present invention and the ‘978 application is that the ‘978 application also comprise claims drawn to methods of using the claimed product. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. As such, the ‘978 application anticipates the present invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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