DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s correspondence and amendments filed July 27, 2026, is acknowledged. In response to the Restriction Requirement of June 01, 2026, Applicant has elected the invention of Group I, without traverse. Claims 1-2, 6, and 9-10 are presently amended; claims 28-30 are new; and claims 3-4, 11-21, and 23-27 are canceled in view of the election. Accordingly, claims 1-2, 5-10, 22, and 28-30 are presently pending and subject to examination.
Information Disclosure Statement
3. The listing of references in the specification (see e.g., para. [0084]) 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 references should be placed on an information disclosure statement if Applicant would like them considered.
Objection to the Specification
4. The instant specification is objected to for the following reasons:
a. There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “BLAST” at para. [0100]), which is a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology whenever possible; furthermore the terms 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. Please, review the specification for other improper trademarks and correction is required.
b. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see e.g., para. [0084]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
5. Claim 1 (and claims 2, 5-10, 22, and 28-30, which depend thereon) are object to for reciting the term “analysis method of IMGT.” IMGT is a trademark/trade name. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular feature, the claim scope is uncertain since the trademark or trade name cannot be used properly to identify the feature. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a method of determining CDRs and accordingly, the claim is objected to.
Claim Rejections - 35 USC § 112
6. 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
7. Claims 1-2, 5-10, 22, and 28-30 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 claims contain 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.
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.)
No Written Description for the Breath of the Claims: genera “antibody” and fragments thereof (i.e., claims 7 and 9); Applicant is only in possession of VHH antibodies (i.e., single chain antibodies or nanobodies) and heavy chain antibodies, and not fragments thereof or other antibody types.
The claims recite “an antibody.” Claim 7 further recites that the antibody has a human Fc region having “an amino acid sequence set forth in SEQ ID NO: 191,” which reads on any subsequence therein. Claim 9 explicitly further recites additional fragments of the “antibody.”
The specification defines the term “antibody” to include any antibody type at para. [0068]-[0070].
The claims therefore broadly encompass not only that the antibody can be of any type, but also that it may be any fragment of the antibody.
The specification teaches identification of VHH domains by phage display at Example 5; and specific binding activity of full heavy chain antibodies at e.g., Tables 21-24. The specification does not disclose the binding activity of any other antibody types, let alone fragments thereof.
The claims recite functional language of the antibody, such as specifically binds to CD33; however, a definition by function does not suffice to define the genus of antibodies because it is only an indication of the antibodies do, rather than what it is. Therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of antibodies and fragments thereof is highly variable (i.e., each would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed antibodies and fragments have no correlation between their structure and function.
The specification only sets forth full VHH antibodies and heavy chain antibodies as potentially having the claimed functionality; however, these species are not sufficiently representative of the genus of antibodies and fragments instantly claimed because: the structure, and therefore binding activity towards CD33, of the encompassed antibody types and fragments thereof will necessarily be highly variable. To address this issue, a brief assessment of the state of the art of (i) unique features of VHH domains vs VH domains of other antibody types and (ii) the general unpredictability of the biological activity of fragments are made herein, which shows it is very unpredictable what binding activity towards CD33 the encompassed antibodies and fragments thereof will have, and therefore it is very unpredictable which ones may specifically bind to CD33.
Regarding (i) the unique features of VHH domains vs VH domains of other antibody types:
Nanobody vs antibody (https://www.tracercro.com/resources/blogs/nanobody-vs-antibody/) is an introduction to nanobody technology. It teaches that a fundamental unique characteristic of VHH antibodies is the long CDR3, which helps compensate for lack of light chain. The relevant information is provided below for Applicant’s convenience:
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Furthermore, Jin et al. ("NANOBODIES®: a review of generation, diagnostics and therapeutics." International journal of molecular sciences 24.6 (2023): 5994) is a review of nanobody technology. Jin et al. teach at section 2, third paragraph: “Another two key structural characteristics of Nbs are the amino acid residue composition of FR2 and the general convex shape of the paratope. While the FR2 of conventional mAb VH domains are largely made up of conserved hydrophobic amino acid residues at conserved positions, namely V37/G44/L45/W47, due to the necessary interaction with the VL domain for functionality, the FR2 of Nbs typically consist of hydrophilic amino acid residues, namely F37/E44/R45/G47, that provides an explanation for their ability to exist alone as a soluble monomer. It should also be noted that an amino acid residue substitution of L11 into S11 in the FR1 region is commonly observed (more commonly observed in dromedary VHH sequences than in llama VHH sequences). Furthermore, unlike the concave or flat paratopes that are commonly exhibited by the VH–VL domains of mAbs, the paratopes of Nbs exhibit a convex paratope largely contributed by their extended CDR3 loop.” Jin et al. therefore teach that not only are the framework regions important for structure and therefore binding activity of nanobodies (i.e., VHH antibodies), but that they are also considerably different from those of conventional antibodies. It is therefore unpredictable what binding activity the encompassed “antibodies”—having variable framework regions—will have.
Jin et al. also teach at section 2, first paragraph: “Nbs and VH domains of conventional antibodies share some similar structural traits. Both antibody fragments consist of four conserved framework regions (FR), and three hypervariable complementarity-determining regions (CDR) responsible for determining antigen specificity. These seven regions (FR and CDR) fold into two β-sheets, one consisting of four β-strands and the other of fice β-strands, with the CDRs located in between the β-strands and gathered at the N-terminal of the Nb to form the antigen-binding site, also referred to as the paratope. However, there also exists multiple structural dissimilarities between Nbs and conventional VH fragments, that provide a range of advantages to Nbs when compared to other monoclonal antibodies (mAb) or mAb fragments such as single-chain variable fragments (scFv).” Jin et al. proceed to outline the significant structural differences between the VHH antibodies / heavy chain antibodies demonstrated in the instant specification, and conventional antibodies encompassed by the instant claims, including substantial differences in the framework regions and CDRs. The cited references therefore demonstrate that it is very unpredictable how the instant disclosure may be converted into “antibodies” other than VHH antibodies or heavy chain antibodies. Applicant has not performed any of the required experiments to determine which may work, other than for VHH and heavy-chain antibodies.
Regarding (ii) the general unpredictability of the biological activity of fragments:
Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teach regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid polypeptide would have substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teach regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a polypeptide sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different polypeptide resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible antibody fragments encompassed the claims. Therefore, without performing the required experiments it is wholly unpredictable which antibody fragments may retain biological activity, let alone have specific biding to CD33 as instantly claimed.
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one 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."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (emphasis added). That is the case here because only full VHH antibodies (e.g., nanobodies) and heavy chain antibodies, and not fragments thereof or other antibody types, are demonstrated by the instant specification.
Neither the art nor the specification provides a sufficient representative number of species of (i) antibody types or (ii) fragments thereof having the instantly claimed CDRs or VHHs to meet the written descript requirement for instant claims directed to “antibodies” and fragments thereof. Therefore, without performing any of the required experiments, it is unknown which of the encompassed antibodies and fragments thereof having the instantly claimed CDRs will result in an antibody that specifically binds to CD33. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of “antibodies” and fragments thereof encompassed by the claims.
No Written Description for the Breath of the Claims: genera of heavy chain antibodies comprising constant regions other than the human IgG1 Fc of SEQ ID NO: 191 (e.g., claims 6, 28, 29); Applicant is in possession of the subject matter of claim 7.
Claims 6, 28, and 29 are directed to “wherein the antibody heavy chain constant region is selected from the group consisting of human, Vicugna pacos, mouse, rat, rabbit, and sheep” (i.e., claim 6); heavy chains selected from various immunoglobulins (i.e., claim 28); and “wherein the heavy chain constant region is selected from the group consisting of an Fc region, a CH3 region, a heavy chain constant region without a CH 1 fragment, and an intact heavy chain constant region) (i.e., claim 29).
The claims therefore broadly encompass that the constant region of the heavy chain antibodies can be from various species, various immunoglobulins, and have various configurations, e.g., excluding the CH2 region.
The specification teaches specific binding activity of full heavy chain antibodies having the human IgG1 Fc of SEQ ID NO: 191 at e.g., Tables 21-24. The specification does not disclose the binding activity of heavy chain antibodies having any other configuration.
The claims recite functional language of the antibody, such as specifically binds to CD33; however, a definition by function does not suffice to define the genus of antibodies because it is only an indication of the antibody does, rather than what it is. Therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of antibodies is highly variable (i.e., each would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed antibodies and fragments have no correlation between their structure and function.
The specification only sets forth heavy chain antibodies having the human IgG1 Fc of SEQ ID NO: 191 as potentially having the claimed functionality; however, these species are not sufficiently representative of the genus of antibodies instantly claimed because: the variable structures of the Fc domains encompassed by the claims are expected to affect the binding properties of the instantly claimed heavy chain antibodies. To address this issue, a brief assessment of the state of the art of heavy chain constant regions is made herein, which shows it is very unpredictable what binding activity towards CD33 the encompassed heavy chain antibodies having variable constant regions will have, and therefore it is very unpredictable which ones may specifically bind to CD33.
Torres et al. ("The immunoglobulin heavy chain constant region affects kinetic and thermodynamic parameters of antibody variable region interactions with antigen." Journal of Biological Chemistry 282.18 (2007): 13917-13927) is a journal article regarding the role of heavy chain constant region in antigen binding (see the title). The abstract of Torres et al. teaches: “A central dogma in immunology is that antibody specificity is a function of the variable (V) region. However serological analysis of IgG1, IgG2a, and IgG2b switch variants of murine mono clonal antibody (mAb) 3E5 IgG3 with identical V domains revealed apparent specificity differences for Cryptococcus neoformans glucuronoxylomannan (GXM). Kinetic and thermodynamic binding properties of mAbs 3E5 to a 12-mer peptide mimetic of GXM revealed differences in the affinity of these mAbs for a monovalent ligand, a result that implied that the constant (C) region affects the secondary structure of the antigen binding site, thus accounting for variations in specificity.” Torres et al. therefore teach that the constant region affects antibody binding, e.g., the specific binding properties to CD33 of the instantly claimed antibodies. For example, it is wholly unknown how the encompassed antibodies having constant regions without CH3 domains (i.e., claim 29) may bind to CD33 because Applicant has only demonstrated heavy chain antibodies having the human IgG1 Fc of SEQ ID NO: 191.
Furthermore, Janeway et al. ("Immunobiology." (2001)) is a textbook that discusses the structural variability between immunoglobulin classes. Janeway et al. shows at FIG. 4.17 that IgG, IgM, IgD, IgA1, and IgE have substantial structural variability. Janeway et al. also shows at FIG. 4.23 that IgM and IgA also may form unique multimers that will affect binding activity, which is reproduced below for Applicant’s convenience:
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Janeway et al. therefore demonstrate that there is substantial structural variability, and therefore substantial variability in binding properties, between the encompassed immunoglobulin subclasses.
Further, Vidarsson et al. ("IgG subclasses and allotypes: from structure to effector functions." Frontiers in immunology 5 (2014): 520) is a review of IgG subclasses. FIG 3 of Vidarsson et al. shows that there is significant amino acid sequence variability in the Fc domains (i.e., CH2-CH3) between IgG subclasses, let alone between the IgGs of different species as encompassed by the instant claims. FIG 3 of Vidarsson et al. shows that e.g., only 50% of the IgG1 Fc sequence corresponds to the IgG4 Fc sequence. Vidarsson et al. therefore further demonstrate that there will be significant structural variability and therefore variable binding properties of the encompassed heavy chain antibodies having variable constant regions.
Neither the art nor the specification provides a sufficient representative number of species of the instantly claimed VHH/CDRs connected to variable heavy chain constant regions to meet the written descript requirement for instant claims directed to such subject matter. Therefore, without performing any the required experiments, it is unknown which of the encompassed heavy chain constant regions other than human IgG1 Fc of SEQ ID NO: 191 will result in a heavy chain antibody that specifically binds to CD33. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of heavy chain constant regions encompassed by the claims.
Given all of the above, the cited references demonstrate that Applicant is not in possession of the breadth of the instantly claimed subject matter. Applicant is in possession of: VHH antibodies (i.e., single domain antibodies / nanobodies) and heavy chain antibodies further comprising the human IgG1 Fc of SEQ ID NO: 191; and no fragments thereof.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and 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. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Scope of Enablement
8. Claims 1-2, 5-10, 22, and 28-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for VHH antibodies (i.e., single domain antibodies / nanobodies) and heavy chain antibodies further comprising the human IgG1 Fc of SEQ ID NO: 191; and no fragments thereof, does not reasonably provide enablement for “antibodies” comprising the claim-recited CDRs, antibodies comprising variable heavy chain regions, or fragments thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claims:
The claims are drawn to an antibody or an antigen-binding fragment specifically binding to CD33, comprising specified CDR1s, CDR2s, and CDR3s. The claims characterize the antibody or antigen binding fragment as having a specified binding activity to human and monkey CD33 at claim 5; and that the antibody is a heavy chain antibody at claim 8. The claims recite various features of a heavy chain constant region at claims 6, 7, 28, and 29; and further fragments of the antibody or antigen-binding fragment are recited at claim 9.
The claims are therefore broad and encompass that the antibody or antigen binding fragment can: be of any antibody type; have highly variable heavy chain constant regions (when present); or be a fragments of the antibody or antigen-binding fragments that specifically bind to CD33.
(5) The predictability or unpredictability of the art:
The state of the art indicates it is very unpredictable how well members of the genera “antibodies,” and further fragments thereof encompassed by the claims—other than VHH antibodies or heavy chain antibodies having specific constant regions—will specifically bind to CD33.
It is unpredictable which members of genera “antibody” and fragments thereof (i.e., claims 7 and 9) may specifically bind to CD33; Applicant has only shown how to make and use VHH antibodies (i.e., single chain antibodies or nanobodies) and heavy chain antibodies, and not fragments thereof or other antibody types.
The claims recite “an antibody.” Claim 7 further recites that the antibody has a human Fc region having “an amino acid sequence set forth in SEQ ID NO: 191,” which reads on any subsequence therein. Claim 9 explicitly further recites additional fragments of the “antibody.” The specification defines the term “antibody” to include any antibody type at para. [0068]-[0070].
In view of this, a brief assessment of the state of the art of (i) unique features of VHH domains vs VH domains of other antibody types and (ii) the general unpredictability of the biological activity of fragments are made herein, which shows it is very unpredictable what binding activity towards CD33 the encompassed antibodies and fragments thereof will have, and therefore it is very unpredictable which ones may specifically bind to CD33.
Regarding (i) the unique features of VHH domains vs VH domains of other antibody types:
Nanobody vs antibody (https://www.tracercro.com/resources/blogs/nanobody-vs-antibody/) is an introduction to nanobody technology. It teaches that a fundamental unique characteristic of VHH antibodies is the long CDR3, which helps compensate for lack of light chain. The relevant information is provided below for Applicant’s convenience:
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Furthermore, Jin et al. ("NANOBODIES®: a review of generation, diagnostics and therapeutics." International journal of molecular sciences 24.6 (2023): 5994) is a review of nanobody technology. Jin et al. teach at section 2, third paragraph: “Another two key structural characteristics of Nbs are the amino acid residue composition of FR2 and the general convex shape of the paratope. While the FR2 of conventional mAb VH domains are largely made up of conserved hydrophobic amino acid residues at conserved positions, namely V37/G44/L45/W47, due to the necessary interaction with the VL domain for functionality, the FR2 of Nbs typically consist of hydrophilic amino acid residues, namely F37/E44/R45/G47, that provides an explanation for their ability to exist alone as a soluble monomer. It should also be noted that an amino acid residue substitution of L11 into S11 in the FR1 region is commonly observed (more commonly observed in dromedary VHH sequences than in llama VHH sequences). Furthermore, unlike the concave or flat paratopes that are commonly exhibited by the VH–VL domains of mAbs, the paratopes of Nbs exhibit a convex paratope largely contributed by their extended CDR3 loop.” Jin et al. therefore teach that not only are the framework regions important for structure and therefore binding activity of nanobodies (i.e., VHH antibodies), but that they are also considerably different from those of conventional antibodies. It is therefore unpredictable what binding activity the encompassed “antibodies”—having variable framework regions—will have.
Jin et al. also teach at section 2, first paragraph: “Nbs and VH domains of conventional antibodies share some similar structural traits. Both antibody fragments consist of four conserved framework regions (FR), and three hypervariable complementarity-determining regions (CDR) responsible for determining antigen specificity. These seven regions (FR and CDR) fold into two β-sheets, one consisting of four β-strands and the other of fice β-strands, with the CDRs located in between the β-strands and gathered at the N-terminal of the Nb to form the antigen-binding site, also referred to as the paratope. However, there also exists multiple structural dissimilarities between Nbs and conventional VH fragments, that provide a range of advantages to Nbs when compared to other monoclonal antibodies (mAb) or mAb fragments such as single-chain variable fragments (scFv).” Jin et al. proceed to outline the significant structural differences between the VHH antibodies / heavy chain antibodies demonstrated in the instant specification, and conventional antibodies encompassed by the instant claims, including substantial differences in the framework regions and CDRs. The cited references therefore demonstrate that it is very unpredictable how the instant disclosure may be converted into “antibodies” other than VHH antibodies or heavy chain antibodies. Applicant has not performed any of the required experiments to determine which may work, other than for VHH and heavy-chain antibodies.
Regarding (ii) the general unpredictability of the biological activity of fragments:
Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teach regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid polypeptide would have substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teach regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a polypeptide sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different polypeptide resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible antibody fragments encompassed the claims. Therefore, without performing the required experiments it is wholly unpredictable which antibody fragments may retain biological activity, let alone have specific biding to CD33 as instantly claimed.
It is unpredictable which heavy chain antibodies comprising constant regions other than the human IgG1 Fc of SEQ ID NO: 191 may specifically bind to CD33 (e.g., claims 6, 28, 29); Applicant has only shown how to make and use the subject matter of claim 7.
Claims 6, 28, and 29 are directed to “wherein the antibody heavy chain constant region is selected from the group consisting of human, Vicugna pacos, mouse, rat, rabbit, and sheep” (i.e., claim 6); heavy chains selected from various immunoglobulins (i.e., claim 28); and “wherein the heavy chain constant region is selected from the group consisting of an Fc region, a CH3 region, a heavy chain constant region without a CH 1 fragment, and an intact heavy chain constant region) (i.e., claim 29). In contrast, Applicant only demonstrates the use of heavy chain antibodies having the human IgG1 Fc of SEQ ID NO: 191.
In view of this, a brief assessment of the state of the art of heavy chain constant regions is made herein, which shows it is very unpredictable what binding activity towards CD33 the encompassed heavy chain antibodies having variable constant regions will have, and therefore it is very unpredictable which ones may specifically bind to CD33.
Torres et al. ("The immunoglobulin heavy chain constant region affects kinetic and thermodynamic parameters of antibody variable region interactions with antigen." Journal of Biological Chemistry 282.18 (2007): 13917-13927) is a journal article regarding the role of heavy chain constant region in antigen binding (see the title). The abstract of Torres et al. teaches: “A central dogma in immunology is that antibody specificity is a function of the variable (V) region. However serological analysis of IgG1, IgG2a, and IgG2b switch variants of murine mono clonal antibody (mAb) 3E5 IgG3 with identical V domains revealed apparent specificity differences for Cryptococcus neoformans glucuronoxylomannan (GXM). Kinetic and thermodynamic binding properties of mAbs 3E5 to a 12-mer peptide mimetic of GXM revealed differences in the affinity of these mAbs for a monovalent ligand, a result that implied that the constant (C) region affects the secondary structure of the antigen binding site, thus accounting for variations in specificity.” Torres et al. therefore teach that the constant region affects antibody binding, e.g., the specific binding properties to CD33 of the instantly claimed antibodies. For example, it is wholly unknown how the encompassed antibodies having constant regions without CH3 domains (i.e., claim 29) may bind to CD33 because Applicant has only demonstrated heavy chain antibodies having the human IgG1 Fc of SEQ ID NO: 191.
Furthermore, Janeway et al. ("Immunobiology." (2001)) is a textbook that discusses the structural variability between immunoglobulin classes. Janeway et al. shows at FIG. 4.17 that IgG, IgM, IgD, IgA1, and IgE have substantial structural variability. Janeway et al. also shows at FIG. 4.23 that IgM and IgA also may form unique multimers that will affect binding activity, which is reproduced below for Applicant’s convenience:
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Janeway et al. therefore demonstrates that there is substantial structural variability, and therefore substantial variability in binding properties, between the encompassed immunoglobulin subclasses.
Further, Vidarsson et al. ("IgG subclasses and allotypes: from structure to effector functions." Frontiers in immunology 5 (2014): 520) is a review of IgG subclasses. FIG 3 of Vidarsson et al. shows that there is significant variability in the Fc domains (i.e., CH2-CH3) between IgG subclasses, let alone between the IgGs of different species as encompassed by the instant claims. FIG 3 of Vidarsson et al. shows that e.g., only 50% of the IgG1 Fc sequence corresponds to the IgG4 Fc sequence. Vidarsson et al. therefore demonstrates there will be significant structural variability and therefore variable binding properties of the encompassed heavy chain antibodies having variable constant regions.
Given all of the above, the cited referenced demonstrate that it is very unpredictable which of the encompassed heavy chain constant regions—other than the human IgG1 Fc of SEQ ID NO: 191—will result in a heavy chain antibody that specifically binds to CD33. Applicant has not performed the required experiments to teach one of ordinary skill in the art how to make and use a sufficient number of species of the antibodies encompassed by the claims.
6) the amount of direction or guidance provided by the inventor:
The specification only discloses specific binding to CD33 of VHH antibodies and heavy chain antibodies having the human IgG1 Fc of SEQ ID NO: 191. The specification fails to disclose any fragments thereof, alternative heavy chain constant regions, or other antibody types comprising the claim-recited CDRs.
Given all of the above, on of skill in the art could not reasonably extrapolate the instant findings regarding CD33 binding affinities achieved with VHH antibodies and heavy chain antibodies having the human IgG1 Fc of SEQ ID NO: 191 to the breadth of the claim-recited “antibodies” and fragments thereof. It would be undue experimentation to determine which of the encompassed antibodies would specifically bind to CD33.
8) the quantity of experimentation needed to make or use the invention:
It would be undue experimentation to make or use the invention encompassed by the breadth of the claims because each of the fragments of different antibody types, and having variable heavy chain constant regions, would need to be made and then tested for specific binding to CD33. In contrast, Applicant has only demonstrated specific binding to CD33 of VHH antibodies and heavy chain antibodies having a single heavy chain constant region. The above-cited references demonstrate that is unpredictable which of the other antibodies encompassed by the claims will also have specific biding to CD33.
In conclusion, the claimed invention does not provide enablement for “antibodies” comprising the claim-recited CDRs, antibodies comprising variable heavy chain regions, or fragments thereof. The claimed invention only provides enablement for VHH antibodies (i.e., single domain antibodies / nanobodies) and heavy chain antibodies further comprising the human IgG1 Fc of SEQ ID NO: 191; and no fragments thereof. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
9. 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 7 is rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 7 recites that the human Fc region has “an amino acid sequence set forth in SEQ ID NO: 191.” It is unclear if the term “an” means that the Fc region may comprise any two consecutive amino acids of SEQ ID NO: 191, or that the human Fc region must comprise the entire / exact amino acid sequence of SEQ ID NO: 191. Does claim 7 encompass Fc domains other than the Fc domain of SEQ ID NO: 191? Appropriate clarification and/or correction is required.
Conclusion
10. No claim is allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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