DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 5, 10-24, 35, and 37 are cancelled. Claims 1-4, 6-9, 25-34, 36, and 38 as filed on 28 December 2023 are pending and under examination.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 29 and 38 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 29 contains the trademark/trade name Nanobody. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. 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 of VHH and, accordingly, the identification/description is indefinite.
Claim 29 recites a linear antibody. The art teaches linear epitopes which are recognized by antibodies based on linear sequence of antibodies, primary structure, in contrast with conformational epitopes that have specific three-dimensional shape or tertiary structure. The art does not provide the use of a linear antibody.
Claim 38 recites the parentheticals: celiac disease (gluten-sensitive bowel disease)”; “unwanted/unintended immune reactions to therapeutic proteins (e.g., factor VII in hemophilia)”; “Rich-Strauss syndrome (allergic granulomatosis)”.
These parentheticals render the claim indefinite because it is unclear whether the limitation within the parenthetical is preferred example –and therefore not limiting—or is part of the claimed invention. Examiner notes that Churg-Strauss syndrome was renamed to allergic granulomatosis and cannot find art using the term “Rich-Strauss”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 8 and 29 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 8 depends from claim 7. Claim 7 is to antibodies that bind CD40 with fully defined CDRs of the heavy and light chain.
Claim 8 defines the antibodies as comprising CDRs with up to 5 amino acid substitutions in each CDR. The antibodies of claim 8 fail to include all the requirements of claim 7.
Claim 29 recites the trademark name nanobody, which the common name for is a VHH which comprise a heavy chain only and three CDRs. Claim 29 depends from claim 1 which recites an antibody comprising a heavy and light chain. A VHH would not include all of the limitations of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 6, 25-34, 36, and 38 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.
MPEP § 2163 states that 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, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
Claim 1 is to an anti-CD40 antibody or antigen-binding fragment that allows for amino acid substitutions in all 6 CDRs and for the mixing and matching of the resulting CDR sequences.
Claim 2 is to an anti-CD40 antibody or antigen-binding fragment with mixing and matching of fully defined CDRs in the heavy and light chain.
Claim 3 is to an anti-CD40 antibody or antigen-binding fragment with mixing and matching of heavy and light chains with fully defined CDR sequences.
Claim 4 is to an anti-CD40 antibody or antigen-binding fragment that allows for up to 5 amino acid substitutions in the CDRs of the heavy and light chain.
Claim 5 depends from claim 1 and allows for mixing and matching of partially defined VH and VL sequences allowing for variation in the combination of VH and VLs and variation in the CDR sequences of the heavy and light chains in lines 3-7. Subparts (i)-(x) limits the CD40 binding antibodies to specific pairs of heavy and light chains they still allow for variation in the CDRs of the heavy and light chain.
Claims 25-34, 36, and 38 depend from claim 1 and does not provide further limitations on the CDRs of the heavy or light chain.
Summary of Species Disclosed in the original specification
Applicant discloses 39 CD40 binding CDR combinations that work in an antibody or antigen-binding fragment they are shown in Table 2 of the application and Figures 1-9 and shown below.
Heavy Chain
Light Chain
SEQ ID NO:
CDR1
CDR2
CDR3
CDR1
CDR2
CDR3
D1
1
9
32
58
65
70
D2
4
27
53
62
67
78
D3
5
27
54
62
67
78
D4
6
28
55
63
68
79
D5
7
29
56
64
69
80
D6
8
30
57
62
67
80
D7
4
31
53
62
68
79
D11
1
9
32
58
65
70
D21
1
10
32
58
65
70
D22
1
11
33
58
65
71
D23
1
9
34
58
66
72
D24
1
12
35
59
65
70
D25
2
9
32
58
65
70
D26
1
13
34
59
65
70
D27
1
14
36
60
65
70
D28
1
15
37
59
65
73
D29
1
16
38
59
65
74
D30
1
17
39
59
65
70
D31
1
18
40
59
65
70
D32
1
19
41
59
65
70
D33
1
20
42
59
65
70
D34
1
9
37
59
65
75
D35
3
9
32
58
65
70
D36
1
9
43
61
65
70
D37
1
21
32
59
65
70
D38
1
22
44
59
65
70
D39
1
9
45
59
65
70
D40
1
11
46
59
65
70
D41
1
15
47
59
65
76
D42
1
14
43
59
65
70
D43
1
23
48
59
65
70
D44
1
9
49
59
65
70
D45
1
18
50
59
65
77
D46
1
15
51
59
65
70
D47
1
11
48
59
65
71
D48
1
24
34
61
65
70
D49
1
18
47
59
65
71
D50
1
25
52
59
65
70
D51
1
26
34
59
65
70
State of the Relevant Art
CD40 is a co-stimulatory molecule belonging to the tumor necrosis factor (TNF) receptor superfamily and is precent on antigen presenting cells (APCs). APCs are activated when CD40 binds it ligand CD40L. CD40 mediated APC activation is involved in a variety of immune responses including cytokine production, up-regulation of co-stimulatory molecules, and enhanced antigen presentation and B cell proliferation. CD40 is also expressed on endothelial cells, smooth muscle cells, fibroblasts, and epithelial cells. CD40 activity is also involved in undesired T cell responses related to autoimmunity, transplant rejection, or allergic responses. A known in the art strategy for controlling undesirable T cell responses is to target CD40 with an antagonistic antibody. Antagonistic antibodies to CD40 are known in the art and being further developed (Yamniuk WO 2020106620 A1) (IDS) Abstract, [0004]-[0005] and Figures 1-2).
It has been well established in the art that the formation of an intact antigen-binding site in a conventional antibody requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (PTO-892) (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule”, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure of each monoclonal antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). The epitope of an antibody does not provide structure or sequence information about the antibody that binds it.
Further, the skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Brown et al., J. Immunol., 156(9):3285- 91 (1996) (PTO-892). Brown teaches that although a single amino acid change in CDR2 of heavy chain of a particular antibody was tolerated, the antibody lost binding upon introduction of two amino acid changes in the same region. Brown, p. 3290 and Tables 1 and 2. Table 1 of Brown shows that even a conservative substitution does not ensure that functionality of the antibody is retained. These older citations are supported my more recent discoveries of why these substitutions change antibody activity. Marvin et. al., Biochemistry, 42(23):7077-7083 (2003) (“Marvin” PTO-892) teaches that changes to the heavy and light chains altered binding affinity (Table 2) with changes to the CDR having large impacts but the changes with the largest impact were from residues in the CDR, but not from ones interfacing with the antigen ( Page 7081 in col 1 “Conclusions and Discussion” and Page 7082 in Figure 4).
This is confirmed by Chiu et al., Antibodies, 8(55):1-80. (2019) (“Chiu” PTO-892). Chiu teaches that the complementarity-determining regions (HCDRs 1-3 and LCDRs 1-3) determine antigen binding requiring specific sequences and orientation of those sequences to properly form tertiary structures that can recognize and bind antigens (Page 4 in 1.2.2 first and last paragraphs and Figure 3). Chiu teaches that antibody modeling with known LCDRs 1-3, HCDR1 and HCDR2 could not predict HCDR3. The field has shown repeatedly over decades that Structure-Based antibody engineering is unable to predict antibody sequences (Page 6 in 1.2.6, Pages 10-11 in Section 2 in particular second paragraph of page 11). Chiu notes the advancement in antibody engineering but notes it is still not possible to predict the point mutations that would improve affinity in both antibodies and multispecific molecules (Page 51 in lines 6-12).
In general, absent at least the conserved structure of the CDRs of the heavy chain and light chain of an antibody, the skilled artisan generally would not be able to visualize or otherwise predict an antibody with a particular set of functional properties would look like structurally. An epitope does not inform one of skill in the art of the structure of the antibody that binds it and a partial structure of only some CDRs or some of the CDR sequences does not provide sufficient information to identify the undefined CDR identity.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that 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 specification discloses 31 CD40 binding antibodies or antigen binding fragments that all comprise fully defined sets of 6 CDRs.
Given the variability encompassed by the genus of antibodies that bind CD40 where changes to the CDRs change the binding activity in unpredictable ways the described species cannot be considered representative of the genus as the description of an antibody with its fully defined CDRs only provides written description on that antibody and not ones with varying CDR sequences either with substitutions in the sequence or mixing and matching of defined CDRs or heavy and light chains.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
As described above the structure in an antibody that provides its binding activity
is the set of 6 CDRs. As changes to the amino acids of the CDRs change its function, the CDRs of the disclosed antibodies do not disclose additional antibodies. The epitope of an antibody or activity upon binding a target, no matter how specific, does not provide any structure for the CDRs of an antibody that binds that epitope.
Conclusion:
For all of the reasons presented above, one of skill in the art would not know which of the CDR combinations of the claims would meet the structural and functional requirements of the claims. The applicant has not provided a representative number of species for all antibodies that bind CD40. The functional structure of an antibody are its 6 CDRs that provide its binding activity based on the sequences of those CDRs, the CDRs of one antibody do not provide one of skill in the art with the functional CDRs of additional antibodies so the variability of the CDRs of the rejected claims mean there is no structure/function correlation, and the disclosed species do not provide written description for additional antibodies. By allowing variability in the CDRs of the heavy and light chain the instant claims do not have a shared structure that provides the binding activity of the antibodies. The disclosure of 31 CD40 binding antibodies only provides written description for those species disclosed and not the genus of the claims as the CDRs of an antibody only provide written description for that combination of CDRs as variations to CDR sequences change its binding activity in unpredictable ways. Given the nature of the art of antibodies where three CDRs of the heavy chain and three CDRs of the light chain in sets of 6 are the structure that provide its binding function and that the disclosure of one antibody does not provide support for antibodies of even similar sequence, the disclosed 31 species do not provide written description for the antibodies as claimed. Applicant was not in possession of the invention as claimed.
Claims 7 and 9 are not included in this rejection as they are limited to antibodies or antigen binding fragments with fully defined CDRs of the light and heavy chain with no substitutions or mixing and matching of either CDRs or heavy and light chains.
Allowable Subject Matter
Claims 7 and 9 are allowed.
Claims 7 and 9 are to antibody or antigen binding fragments that bind CD40 and comprise the heavy and light chain CDRs as shown in the table below. In view of the CDR definitions of Table 1 the antibodies or antigen binding fragments of claim 1 are fully defined and shown to bind CD40.
SEQ ID NO:
Heavy Chain CDRs
Light Chain CDRs
D2
120
139
D3
121
140
D4
122
141
D5
123
142
D6
124
143
D7
125
144
The closes prior art is Yamniuk WO 2020106620 A1) (IDS). Yamniuk teaches CD40 binding antibodies (Abstract and Figures 1-2). Yamniuk does not teach the CDRs of the claimed CD40 binding antibodies or antigen binding fragments either alone or in combination with other art. Changes to CDR regions of antibodies and antigen binding fragments are unpredictable and change the binding specification and activity upon binding of the antibody. It is not obvious to modify the antibodies of Yamniuk to arrive at the instant claimed antibodies.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA EDGINGTON-GIORDANO whose telephone number is (571)272-8232. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
Prosecution Insights