DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant’s amendment, filed on 7/24/2026, is acknowledged.
3. Claims 1-2, 4-5, 7, 10, 13, 17, 18, 22, 24, 25, 29-30, 33, 36, 45 and 46 are pending.
4. Applicant’s election without traverse of Group I, claims 1, 2, 4, 5, 7, 10, 13, 17, 18, 22, 22, 24 and 36 directed to an isolated Gmd-binding antibody and the species of anti-GmD antibody comprising VH, HCDR1-3 and H-FR1-4 of SEQ ID NOs: 7. 10-12 and 13, 18, 21, 23 and VL, LCDR1-3 and L-FR1-4 of SEQ ID NOs: 35, 42-44, and 44[45], 49, 55 and 61, filed on 7/24/2026, is acknowledged.
5. Claims 25, 29-30, 33 and 45-46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
6. Claims 1, 2, 4, 5, 7, 10, 13, 17, 18, 22, 22, 24 and 36 are under examination as they read on an isolated Gmd-binding antibody and the species of anti-Gmd antibody comprising VH, HCDR1-3 and H-FR1-4 of SEQ ID NOs: 7. 10-12 and 13, 18, 21, 23 and VL, LCDR1-3 and L-FR1-4 of SEQ ID NOs: 35, 42-44, and 44 [45], 49, 55 and 61.
7. Applicant’s IDS, filed 08/09/2023, is acknowledged.
8. The specification is objected to under on page 116, because under clone X12, VL FR1 “EIVLTQSPDFQSVTPKEKVTITC” is SEQ ID NO: 45 not SEQ ID NO: 44. Correction is required.
9. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
10. Claims 1, 2, 4, 5, 7, 10, 13, 17, 18, 22, 22, 24 and 36 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
The recitation “VL comprising a VH-CDRx” in claim 1 is ambiguous. It is not clear how a VL would comprise a VH. It appears that the claim should recited “VL comprising a VL-CDRx”
11. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
12. Claims 1, 2, 4, 5, 7, 13, 17, 18, 22, 22, 24 and 36 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims use open language “comprises”, “a VH-CDRx comprising SEQ ID NO: X”, “a VH framework x sequence of SEQ ID NO: X” and “a framework Y sequence of SEQ ID NO:X” the phrase results in an antibody comprising the claimed antibody or any portion of the claimed “SEQ ID NO: X”.
Claim 1 encompasses a broad genus of humanized known Gmd-binding antibody, 1C11, comprising less than the required humanized eight frameworks of the VH and VL; as well as humanized only one framework in either the VH or VL.
Claim 2 encompasses a broad genus of humanized known Gmd-binding antibody, 1C11, comprising up to 3 humanized Frameworks in the VH region.
Claim 4 encompasses a broad genus of humanized known Gmd-binding antibody, 1C11, comprising up to 4 humanized VH frameworks or mixing and matching between different humanized VHs of SEQ ID NOs: 1-8 and humanized VLs of SEQ ID NO: 33-40.
Claim 5 encompasses a broad genus of humanized known Gmd-binding antibody, 1C11, comprising only two humanized VL frameworks and lacking the other 6 humanized frameworks.
Claim 7 encompasses a broad genus of humanized known Gmd-binding antibody, 1C11, comprising up to10% modification in the humanized VH of SEQ ID NOs: 1-8 and humanized VL of SEQ ID NOs: 33-40; as well as up to 15 amino acid variations in the humanized VH of SEQ ID NO: 1-8 and/or up to 15 amino acid variations in the humanized VL of SEQ ID NOs: 33-40.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of Gmd-binding. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear 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, reduction to drawings, or 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 genus.
The claims use open language “comprises”, “a VH-CDRx comprising SEQ ID NO: X”, “a VH framework x sequence of SEQ ID NO: X” and “a framework Y sequence of SEQ ID NO:X” the phrase results in an antibody comprising the claimed antibody or any portion of the claimed “SEQ ID NO: X”.
The claim terminology “a VH-CDRx comprising SEQ ID NO: X”, “a VH framework x sequence of SEQ ID NO: X” and “a framework Y sequence of SEQ ID NO:X” does not place size limits on the VH/VL/CDRs and VH/VL frameworks, but rather reads on any portion of the claimed VH/ VL/ CDRs/frameworks of SEQ ID NO. The VH/VL/CDRs /frameworks are generic with respect to size, encompassing anything from dimers on up to the full size of the claimed SEQ ID NOs. It is suggested that the claims amended to recited the article “a” with “the” to overcome this portion of the rejection.
The specification provides 27 versions of humanized 1C11 antibody.
CLONE
X4
X13
X5
X6
X14
X7
X8
X12
X28
X29
X9
X10
X11
X24
VH
1
1
2
2
2
3
3
3
3
3
4
5
5
5
H-FW1
13
13
13
13
13
14
14
14
14
14
14
14
14
14
H-FW2
17
17
17
16
16
16
16
16
16
16
17
18
18
18
H-FW3
21
21
21
21
21
21
21
21
21
21
21
21
21
21
H-FW4
23
23
23
23
23
23
23
23
23
23
23
23
23
23
VL
34
35
34
37
35
33
39
33
38
36
39
39
35
38
L-FW1
46
45
46
47
45
45
47
45
47
46
47
47
45
47
L-FW2
50
49
50
50
49
49
51
49
50
50
51
51
49
50
L-FW3
54
55
54
56
55
53
58
53
57
55
58
58
55
57
L-FW4
61
61
61
61
61
61
61
61
61
61
61
61
61
61
X25
X15
X26
X27
X16
X17
X18
X19
X21
X22
X23
X30
X31
1C11
5
6
6
6
7
7
8
8
8
8
8
8
8
9
14
13
13
13
13
13
13
13
13
13
13
13
13
15
18
17
17
17
18
18
19
19
19
19
19
19
19
20
21
21
21
21
21
21
21
21
21
21
21
21
21
22
23
23
23
23
23
23
23
23
23
23
23
23
23
23
36
35
38
36
35
34
35
33
37
34
40
39
36
41
46
45
47
46
45
46
45
45
47
46
46
47
46
48
50
49
50
50
49
50
49
49
50
50
57
50
50
52
55
55
57
55
55
54
55
53
56
54
59
57
55
60
61
61
61
61
61
61
61
61
61
61
61
61
61
61
Claim 1 encompasses a broad genus of humanized known Gmd-binding antibody, 1C11, comprising less than the required humanized eight frameworks of the VH and VL; as well as humanized only one framework in either the VH or VL.
In humanization, the complementarity-determining regions (CDRs) from a non-human antibody are transplanted onto the framework regions (FWRs) of a human antibody. Frameworks with the highest sequence homology to the original murine antibody are typically selected as the acceptor scaffold. However, loss of antigen-binding affinity after humanization can happen. Vernier zone residues play a critical role in supporting the correct conformation of CDR loops. These vernier zone residues are located in β-sheet regions underlying the CDRs and can significantly influence binding characteristics.
Fernández-Quintero et al (Protein Engineering, Design and Selection, 2019, vol. 32 no. 9, pp. 411–422) studied a Fv without structural information of the anti-idiotypic antibody Ab2/3H6, because it completely lost its binding affinity upon superhumanization, as an example of a failed humanization. Enhanced sampling techniques in combination with molecular dynamics simulations allow to access micro-to milli-second timescales of the CDR-H3 loop dynamics and reveal kinetic and thermodynamic changes involved in the process of humanization. In most cases, Fernández-Quintero et al observe a reduced conformational diversity of the CDR-H3 loop when grafted on a human framework and find a conformational shift of the dominant CDR-H3 loop conformation in solution. A shallow side minimum of the conformational CDR-H3 loop ensemble attached to the murine framework becomes the dominant conformation in solution influenced by the human framework. Additionally, we observe in the case of the failed humanization that the potentially binding competent murine CDR-H3 loop ensemble in solution shows nearly no kinetical or structural overlap with the superhumanized variant, thus explaining the loss of binding (abstract).
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies routinely requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading "Fv Structure and Diversity in Three Dimensions" of record). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce an antibody having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982 (of record)). Rudikoff et al teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Absent any teaching of structure-function relationships, the skilled in the art cannot determine the critical amino acids in the framework in the recited sequence and also possess the recited function. See AbbVie Deutschland GmbH v. Janssen Biotech, Inc. (Fed. Cir. 2014).
The facts of Abbvie parallel the claimed invention and provide significant guidance on the inherent unpredictability of protein engineering and the effect of amino acid substitutions on protein function. Abbvie is similar to the Federal Circuit's discussion in Novozymes A/S et al. v. Dupont Nutrition Biosciences APS et al., 2013 WL 3779376, Case No. 2012-1433, C.A.Fed; in both, the Federal Circuit emphasized the unpredictability in the art associated with changes in a parent enzyme or protein that can be effected at one or more positions in the sequence by amino acid addition, deletion, or substitution with at least nineteen other possibilities, e.g. counting natural amino acid residues. The basis of the unpredictability is rooted in the same principles that make improvements rare, namely that numerous subtle differences between amino acid residues determine protein binding and function. Because the subtle energetic contributions of each of these interactions is extraordinarily difficult to precisely quantify, and because the number of these interactions is so high even for a single protein-protein interface, innumerable small inaccuracies are amplified into unpredictability. This unpredictability is axiomatic in the field of protein engineering.
For example, 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. Ariad, 598 F.3d at 1351 ("[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology."); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity. Moreover, the '128 and '485 patents of AbbVie do not describe any common structural features of the claimed antibodies. The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.
Regarding the amino acid substations in variable region, one skilled in the art have recognized challenge and trade-offs once it is applied in antibody. Rabia et al (Biochem Eng J. 2018 September 15; 137: 365-374) states that optimize antibody properties (affinity, specificity, stability, solubility and effector functions) with amino acid substitutions is challenge and is always trade-offs and states that an outstanding challenge in the field is that optimizing properties such as antibody affinity can lead to defects in other properties such as antibody stability, specificity and solubility. The resulting trade-offs between improvements in some antibody properties and reductions in others highlight that they are often interdependent and cannot be easily separated (introduction). Rabia et al further state given that the maximal chemical diversity of antibody CDRs is unimaginably large (>1078 antibody variants based on 20 different amino acids at ~60 sites in the CDRs), it is extremely challenging to define the sequence determinants of antibody specificity (para 2).
Besides the specific humanized 1C11 versions disclosed in Table 1, the specification fails to describe specific frameworks that would retain the binding to Gmd.
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.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
13. Claims 1, 2, 4, 5, 7, 13, 17, 18, 22, 22, 24 and 36 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 anti-Gmd antibody comprising the VH and VL recited in claim 10, does not reasonably provide enablement for the anti-Gmd antibodies recited in claims 1, 2, 4, 5, 7, 13, 17, 18, 22, 22, 24 and 36. 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.
The Claims encompass millions of modifications in the frameworks of the known anti-Gmd antibody, 1C11.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The claims are directed to a broad class of humanized anti-Gmd antibodies of 1C11 was that the class was defined by its function—the ability to bind to Gmd and treat treating a Staphylococcus infection or a staphylococcus infection associated condition. However, the specification did not give the skilled in the art enough information to choose candidate antibodies from the millions of options and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses only 27 species of humanized anti-Gmd antibodies that share the same 6 CDRs of SEQ ID NOs: 10-12 and 42-44, listed in claim 10; while the claims are directed to a genus of millions of humanized anti-Gmd antibody variants of 1C11.
In Sanofi-Aventisub, the Federal Circuit relied on its prior precedential opinions when determining whether the full scope of a genus was enabled. These decisions included McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091 (Fed. Cir. 2020) (hereafter McRO); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013) (hereafter Wyeth); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019) (hereafter Enzo); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149 (Fed. Cir. 2019) (hereafter Idenix).
The Federal Circuit, citing McRO, provided guidance on the application of enablement to genus claims, holding that “[a]lthough a specification does not need to describe how to make and use every possible variant of the claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range.” Sanofi-Aventisub, 987 F.3d at 1085 (internal quotations omitted). Additionally, the Federal Circuit characterized Wyeth as holding “that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.” Id. at 1086. Similarly, the Federal Circuit characterized Enzo as holding “that the specification failed to teach one of skill in the art whether the many embodiments of the broad claims would exhibit that required functionality.” Id. Finally, the Federal Circuit characterized Idenix as affirming “the district court's determination that the claims had both structural and functional limitations, and that undue experimentation would have been required to synthesize and screen the billions of possible compounds because, given a lack of guidance across that full scope, finding functional compounds would be akin to finding a `needle in a haystack.' ” Id.
This case is akin to the issue in Sanofi-Aventisub, the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a `vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. In the instant case, the specification discloses only 27 species that performed the claimed function by their amino acid sequences, with the claimed genus of millions of different anti-Gmd antibody variations of 1C11. The instant claims are directed to a class of anti-Gmd antibodies that included “a `vast' number of additional antibodies” that the instant specification fails to describe their amino acid sequences.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
14. No claim is allowed.
15. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Lo et al. Internet Resources for the Antibody Engineer. In: Lo, B.K.C. (eds) Antibody Engineering. Methods in Molecular Biology™, vol 248. Humana Press. https://doi.org/10.1385/1-59259-666-5:135.
Lee et al. Deriving a Dose and Reginen for Anti-Glucosaminidase Antibody Passive-Immunization for Patients with Staphylococcus aureus Osteomyelitis. Eur Cell Mater.; 39:96-107, January 2021.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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August 23, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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