Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restrictions
1. Applicant’s election without traverse of Group I (claims 1-10) in the reply filed on 10/21/25 is acknowledged.
2. The requirement is still deemed proper and is therefore made FINAL.
3. Claims 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 10/21/25. Currently claims 1-10 are under consideration.
Priority
4. The instant application has a priority date of January 10, 2020. This application is a 371 of PCT/JP2020/049120, filed December 28, 2020, which claims the benefit of Japanese Patent Application No. 2020-002968, filed January 10, 2020.
Information Disclosure Statement
5. 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 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
Therefore, unless the Examiner on form PTO-892 or Applicant on PTO-1449 cited the references they have not been considered.
6. The Information disclosure Statements (IDS) filed on 8/3/22, 3/1/24, and 1/30/25 have been considered as to the merits before the First Action.
Claim Rejections - 35 USC § 112
7. 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.
8. Claims 1-3 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. Claims 1-3 are drawn to antibody compositions involving “a population of antibodies comprising homogeneous antibodies in which N-linked complex sugar chains attached to asparagine (Asn) at position 297 of CH domains of Fc regions of two heavy chains on the left and the right of each antibody are sugar chains structurally different from each other”.
The written description in this case does not set forth the possession of all antibody populations comprising homogeneous antibodies in which N-linked complex sugar chains are attached to asparagine (Asn) at position 297 of CH domains of Fc regions of two heavy chains on the left and the right of each antibody and are sugar chains structurally different from each other. The disclosure teaches methods to produce specific antibodies or a limited number of antibodies produced by a method entailing specific enzymes and specific sugars. For example, see section 0006 of the specification “The present inventors have completed the present invention by finding that antibodies, each of which has sugar chains structurally different from each other and which have sugar chain structures on the left and the right homogeneous among the antibodies, can be obtained by appropriately adjusting the amount of sugar chain-oxazoline X (sugar chain X in an oxazoline form) for glycosylation reaction, and isolating antibodies each glycosylated at only one heavy chain using a column with FcyRIIIa immobilized thereon, followed by reaction with sugar chain- oxazoline Y (sugar chain Y in an oxazoline form) structurally different therefrom. No technique of preparing a population of structurally homogeneous antibodies each having sugar chains on the left and the right structurally different from each other has been known so far.”
Additionally, the specification does not set forth any additional method for producing the claimed antibody constructs. And the prior art teaches that the antibody production method can be unpredictable. This is exemplified in the teaching of Liu et al. (Biologicals, Vol.44, 2016, pages 163-169) wherein enzyme(s) utilized to produce the claimed antibodies can be inefficient and thus cause the creation of various types of antibodies linked to sugars at the intermediate step.
Claims 1-3 recite any and all homogeneous population of antibodies in which N-linked complex sugar chains attached to asparagine (Asn) at position 297 of CH domains of Fc regions of two heavy chains on the left and the right of each antibody are sugar chains structurally different from each other. Therefore the written description does not reasonably convey the claimed subject matter to one of ordinary skill in the art. Neither the specification nor the claims exemplify every possible homogeneous antibody construct as claimed.
There is no guidance as to what portions of the claimed antibody are required to meet the claimed features or how much modification can occur while maintaining product characteristics with respect to the instant invention.
There is no guidance as to what antibodies other than the ones taught by the specification, if any can be produced and utilized for the intended purpose. As such, claims 1-3 read on an infinite number of antibody embodiments having specified binding characteristics which could result in any number of complexes not taught and enabled by the specification.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, clearly states 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). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision (see page 115).
Without the specific method taught in the disclosure, the skilled artisan cannot envision the detailed genus or structure of the antibodies as claimed, thus conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of production and or isolation. An adequate description requires more than a mere statement that it is part of the invention and a reference to a potential metho The genus of antibodies required to practice the invention is vast. The instant specification discloses batch of antibodies produced and isolated with oxazoline.
The antibody batch produced in the specification does not appear to be deposited, and it is unclear if that batch of antibodies and their function/composition can be predictably replicated. The instant specification does not provide any guidance for, or identify, the shared sequence/structure the antibody genus must have in order for the antibodies to provide function, have immunological reactivity, and be purified with integrity.
The court indicated that while Applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a representative number of molecules falling within the scope of the claimed genus. Therefore the full breadth of the claims, reading on the claimed homogenous antibody population, does not meet the written description provision of 35 USC 112, first paragraph.
Claim Rejections - 35 USC § 102
9. 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.
10. Claim(s) 1-3 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Liu et al. (Biologicals, Vol.44, 2016, pages 163-169).
Liu et al. disclose IgG antibodies containing N-linked glycans on the Fc portion of each heavy chain. The glycan on one heavy chain can either match the glycan on the other heavy chain (symmetrical pairing) or be different (asymmetrical pairing). See abstract. IgG1 is the most common subtype of human IgG antibodies and it requires a glycan attached at Asn 297 in the Fc domain for ADCC (antibody dependent cellular toxicity). Subtle changes in the Fc glycan structure can greatly affect ADCC activity. For example, a HM type glycan in the Fc domain increases IgG clearance rates in humans compared to IgG with complex glycans or those lacking glycans, due to cellular uptake via the mannose receptor. See Introduction – page 163.
The researchers constructed antibody populations with different glycan combinations. See figure 1. The structures included a complex with glycans (CO) on both heavy chains (CO:CO), a structure with a complex glycan on one heavy chain and a HM (HM) structure on the other (HM:CO), and a structure that has HM on both heavy chains (HM:HM). The HM:CO antibody comprises sugar chains that are “structurally different from each other”. Page 164, 1st column.
Regarding a “homogeneous antibody population”, it is noted that section 0013 of the specification defines homogenous as “In this context, the term "homogeneous" means that the population of antibodies comprises 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more, preferably 98% or more, more preferably 99% or more, particularly preferably 100%, of antibody molecules having the same asymmetric sugar chains attached to heavy chains on the left and the right.” This limitation is taught by Liu et al. at least in figure 1 and page 164-1st column, wherein IgG antibodies with different glycan combinations are disclosed. In figure 1, the antibodies with asymmetrical pairing or asymmetric sugar chains is 100% of the antibody molecules - 60% CO:CO and 40% HM:CO; see that last line in figure 1).
In order to determine the impact of Fc HM pairing on antibody clearance in humans, a sensitive MS-based method to quantify HM glycan paired species on antibodies was utilized. See Fig. 2 An endoglycosidase EndoS trims all present forms of complex glycans, leaving N-acetylglucosamine (GlcNAc) with fucose (Fuc) on the heavy chain, as the large majority of complex glycans contain a core fucose residue. See page 165 – Results. Reading on claim 3. This step greatly reduces the mass heterogeneity found among the complex glycans. Since EndoS does not cleave HM glycans, these forms remain intact. The resulting digestion produced three main glycan paired species: symmetrically paired HM (HM:HM), asymmetrically paired HM [HM on one HC and GlcNAc-Fuc on the other R(HM:CO)], and symmetrically paired complex glycans [GlcNAc-Fuc on both HCs (CO:CO)]. Masses of these 3 species are well resolved by ESI-TOF MS. See page 165 – Results.
With regard to claim 2, the population of antibodies comprises 90% or more of the antibodies having N-linked complex sugar chains attached to the Asn at position 297. The researchers disclose that the “Fc glycan pairing illustrated for an antibody containing an overall level of 20% HM in Fig. 1.
With symmetrical pairing, the same glycan form exists on both heavy chains within a single antibody. In the example shown with HM glycan undergoing only symmetrical pairing (HM:HM), the percentage of HM (as determined by glycan mapping or peptide mapping) matches the percentage of antibodies containing HM. Antibodies with only asymmetrical pairing of HM (HM:CO) would have HM on one heavy chain and a different type of glycan (such as complex, CO) on the other heavy chain.
In that case, the percentage of antibodies containing HM would be double the percentage of overall HM. Mixtures of asymmetric and symmetric HM pairing might also exist in an antibody sample. Percentages of antibodies containing HM would be greater than the overall HM level but less than that found with completely asymmetrical pairing. The example shown is for random pairing, where the glycan processing on one heavy chain is completely independent of the other chain. In this case, the percentages of the asymmetrical and symmetrical pairing would follow a binomial distribution. In the case of HM:CO the antibody would contain 20%HM and 80%CO. See pages 164-166.
Claim Rejections - 35 USC § 103
11. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
12. Claim(s) 4-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. Biologicals, Vol.44, 2016, pages 163-169 in view of Du et al. Glycobiology, 2020, Vol.30, No.4, pages 268-279, publication date 7 July 2019.
Please see Liu et al. as set forth above. Liu et al. differ from the instant invention in not specifically teaching a method of producing the antibody populations by an ENGase – oxazoline form.
However, Du et al. teach that the conserved N-glycan on Asn297 of immunoglobulin G (IgG) has significant impacts on antibody effector functions, and is a frequent target for antibody engineering.
Additionally, chemoenzymatic synthesis has emerged as a strategy for producing antibodies with homogenous glycosylation and improved effector functions. Central to this strategy is the use of enzymes with activity on the Asn297 glycan. EndoS and EndoS2, produced by Streptococcus pyogenes, are endoglycosidases with remarkable specificity for Asn297 glycosylation, making them ideal tools for chemoenzymatic synthesis. See abstract.
The method of chemoenzymatic synthesis of IgG was described on page 271: In the first step, an ENGase from GH18 or GH85 hydrolyzes a heterogeneous mixture of glycoforms obtained by any expression system. In a second step, an ENGase with deficient hydrolytic activity (i.e., a glycosynthase mutant) or a wild-type ENGase transfers a synthetic glycan donor bearing a reactive oxazoline moiety to the deglycosylated protein that retains a GlcNAc (+1) from the first step. GH85 ENGases show the same substrate-mediated catalytic mechanism as GH18 ENGases, with the exception that the assisting catalytic residue (D2) is an asparagine instead of an aspartic acid.
The glycosynthase mutants are obtained by mutating this assisting residue in order to abolish the hydrolytic activity of the enzymes. It has been described that mutation of this residue in a wide range of endoglycosidases has similar effects, creating a path to leverage the inherent substrate specificity and catalytic machinery of endoglycosidases to create glycosynthases for myriad applications. These endoglycosidases/glycosynthases exhibit a wide range of specificities for different glycans, allowing their use to be tailored to the desired glycoform.
KSR forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See recent Board decision Ex parte Smith,- USPQ2d-, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396).
Therefore it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to produce the claimed antibody population in a method employing ENGase generating oxazoline forms for modification of said antibodies because Du et al. taught that the glycosynthase mutants are obtained by mutating the assisting residue in order to abolish the hydrolytic activity of the enzymes. And it has been described that mutation of this residue in a wide range of endoglycosidases has similar effects, creating a path to leverage the inherent substrate specificity and catalytic machinery of endoglycosidases to create glycosynthases for a myriad of applications. These endoglycosidases/glycosynthases exhibit a wide range of specificities for different glycans, allowing their use to be tailored to the desired glycoform. See page 271.
With respect to claim 4 steps i, ii, and iii.
Regarding claim 4, step i (cleaving sugar chains): Liu et al. teach this limitation on pages 164-165: an antibody is mixed with EndoS. “The endoglycosidase EndoS trims all present forms of complex glycans, leaving N-acetylglucosamine (GlcNAc) with fucose (Fuc) on the heavy chain, as the large majority of complex glycans contain a core fucose residue. This step greatly reduces the mass heterogeneity found among the complex glycans. Since EndoS does not cleave HM glycans, these forms remain intact. The result of this digestion will be three main glycan paired species: symmetrically paired HM (HM:HM), asymmetrically paired HM [HM on one HC and GlcNAc-Fuc on the other (HM:CO)], and symmetrically paired complex glycans [GlcNAc-Fuc on both HCs (CO:CO)].”
While, Du et al. teach the utility of ENGase and oxazolone. See Chemoenzymatic synthesis of IgG on pages 271-272. “ ……a chemoenzymatic approach was developed in order to obtain homogenous glycoproteins, including therapeutic monoclonal antibodies. A general approach can be described in two steps(Figure1b). In the first step (Applicants claim 4 step i), an ENGase from GH18 or GH85 hydrolyzes a heterogeneous mixture of glycoforms obtained by any expression system. In a second step (Applicant’s claim 4 step ii), an ENGase with deficient hydrolytic activity (i.e., a glycosynthase mutant) or a wild-type ENGase transfers a synthetic glycan donor bearing a reactive oxazoline moiety to the deglycosylated protein that retains a GlcNAc (+1) from the first step.”
Although Du et al. do not specifically recite that step ii (Applicant’s claim 4 step iii) is repeated to modify both heavy chains, Du et al. discloses that the procedure can be employed to design or tailor various glycans: “the glycosynthase mutants are obtained by mutating this assisting residue in order to abolish the hydrolytic activity of the enzymes. It has been described that mutation of this residue in a wide range of endoglycosidases has similar effects, creating a path to leverage the inherent substrate specificity and catalytic machinery of endoglycosidases to create glycosynthases for myriad applications. These endoglycosidases/glycosynthases exhibit a wide range of specificities for different glycans, allowing their use to be tailored to the desired glycoform. See pages 271-272.
Regarding claim 5 – See Liu et al. page 165-166, sections 2.3 and 3.1, figure 3 and figure 4.
Regarding claim 6 – See Liu et al. page 165, section 3.1
Regarding claim 7 – See Du et al. page 271
Regarding claim 8 – See Liu et al. figure 1 wherein sugar chain X (HM glycan) is larger than sugar chain Y (CO glycan).
Regarding claim 9 – See Liu et al. figure 1
Regarding claim 10 – See Liu et al. section 2.2
13. For reasons aforementioned, no claims are allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lisa Cook whose telephone number is 571-272-0816. The examiner works a flexible schedule but can normally be reached on Monday-Friday Chemoenzymatic from 9am to 5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at telephone number 571-270-3505. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Lisa V. Cook
Patent Examiner
Art Unit 1642
Remsen
571-272-0816
1/24/26
/LISA V COOK/Primary Examiner, Art Unit 1642
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