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 .
Status of Claims
Claims 1-10 were originally filed on December 21st 2020.
The amendment filed on November 15th 2024, amended claims 1-3 and 5-10, added new claims 11-13.
The amendment filed on July 24th 2025, amended claims 1-13 and added new claims 14-16.
The amendment filed on February 27th 2026, cancelled claims 3, 9, 11-12 and 14; and amended claims 1-2, 4-8, 10, 13 and 15-16.
Claims 1-2, 4-8, 10, 13 and 15-16 are currently pending and under consideration.
Priority
The present application is a CON of PCT/JP2019/025701 filed on 06/27/2019.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. JP2018-123981, filed on 06/29/2018.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for Japanese Application JP2018-123981, which papers have been placed of record in the file. Please note that application is in Japanese and thus cannot be verified.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For Claim 1, regarding the scope of “monoclonal antibody,” it is noted that the instant specification does not define what constitutes a “monoclonal antibody.” Rather, the instant specification recites that the term “monoclonal antibody” is a representative of the bioactive substances (See Instant Specification, pg. 1, para[0002]). Additionally, the specification also recites that the polypeptide is a monoclonal antibody (See Instant Specification, pg. 5, line 1). Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. GenScript defines monoclonal antibodies (mAbs) are laboratory-produced antibodies that are designed to target specific antigens with a high degree of precision. These antibodies are created from a single type of immune cell (hence "monoclonal") that is a clone of a parent cell. Hence, the term "monoclonal" refers to the fact that all the antibodies produced are identical and specifically recognize a single target (See GenScript, Biology Terms Dictionary –“Monoclonal antibody”. pp. 1-4 at pg. 1 retrieved from https://www.genscript.com/biology-glossary/10576/monoclonal-antibody on 08/08/24). As such, the Examiner is interpreting the scope of “monoclonal antibody” as a laboratory produced antibody that is specific to a single epitope.
Regarding the scope of a “complex” it is noted that the instant specification does not define what constitutes a “complex.” Rather, the instant specification recites that it is possible to form a complex of the polypeptide and the ligand (See Instant Specification, pg. 5, para[0015], lines 14-15). Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. GenScript teaches that protein complexes consist of two or more protein subunits typically associated with non-covalent interactions (See GenScript, Biology Terms Dictionary- “Complex” pp. 1-3 at pg. 1 retrieved from https://www.genscript.com/biology-glossary/11983/protein-complex on 08/08/2024). As such, the Examiner is interpreting the scope of “complex” as the non-covalent interaction of two or more proteins.
Pursuant to MPEP 2111, the pending claims must be "given their broadest reasonable interpretation consistent with the specification." The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) expressly recognized that the USPTO employs the "broadest reasonable interpretation" standard:
The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must "conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description." 37 CFR 1.75(d)(1).
Regarding the separation method of claim 1, in step C the liquid is filtered, where the filtering step is being interpreted as any filtration method (i.e., micro, ultra, tangential flow, cross flow, etc.).
Regarding dependent claim 6, the separation method which separates the monoclonal antibody from the ligand is being interpreted as the use of any technique that disrupts the non-covalent interaction of the two proteins (i.e., the monoclonal antibody and the ligand). Such separation techniques include but are not limited to centrifugation, precipitation or any type of chromatography.
Response to Arguments
1. Applicants’ arguments, see Response, filed on 02/27/2026, with respect to the objection to claim 1, has been have been fully considered and is persuasive. The objection to claim 1 has been withdrawn.
2. Applicants’ arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention (i.e., indefinity amount of monoclonal antibodies); have been fully considered and are persuasive. The 35 U.S.C. 112(b) rejection to claims 1-16, have been withdrawn.
3. Applicants’ arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention (i.e., indefinite amount of ligands that make up the complex); have been fully considered and are persuasive. The 35 U.S.C. 112(b) rejection to claims 1-16, have been withdrawn.
4. Applicants’ arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention (i.e., indefinite complex); have been fully considered and are persuasive. The 35 U.S.C. 112(b) rejection to claims 1-16, have been withdrawn.
5. Applicants’ arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 112(a) as failing to comply with the written description requirement (i.e., new matter), have been fully considered and are persuasive. The 35 U.S.C. 112(a) rejection to claims 9 is moot.
6. Applicants’ arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 112(a) as failing to comply with the written description requirement (i.e., new matter), have been fully considered and are persuasive. The 35 U.S.C. 112(a) rejection to claims 14 is moot.
7. Applicant’s arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”) as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”); Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”) and Schneider, S., Agilent Technologies, Application Note- Combining small-scale purification and analysis of monoclonal antibodies on one instrument., 2017, pp. 1-8, retrieved from https://www.agilent.com/cs/library/applications/5991-1195EN.pdf?srsltid=AfmBOoqoreIJLM3sbHFheiUNqV0mfdidD3WzrIsZOhfMiYItGCLqoS5n on 11/21/2025 (herein after “Schneider”), have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 1-4, 6-9 and 11-13 has been maintained.
8. Applicant’s arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”) as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”) and Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”) as applied to claim 1, and further in view of JP2009221137 A, published on October 1st 2009, Machine translation (cited in the IDS filed on 12/21/2020) (herein after “Yamaguchi”) and JP2009221137A-Espacenet Machine Translation (herein after “Yamaguchi Espacenet MT”), have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 1 and 5 has been maintained.
9. Applicant’s arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”), as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”) Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”) and Schneider, S., Agilent Technologies, Application Note- Combining small-scale purification and analysis of monoclonal antibodies on one instrument., 2017, pp. 1-8, retrieved from https://www.agilent.com/cs/library/applications/5991-1195EN.pdf?srsltid=AfmBOoqoreIJLM3sbHFheiUNqV0mfdidD3WzrIsZOhfMiYItGCLqoS5n on 11/21/2025 (herein after “Schneider”) as applied to claim 1, and in further view of Batts J.W., The column. 2014, vol. 10, issue 18, pp. 7-10, retrieved from https://www.chromatographyonline.com/view/hplc-systems-zones on 08/10/2024 (herein after “Batts”); have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 1 and 10 has been maintained.
10. Applicant’s arguments, see Response, filed on 02/27/2026, with respect to 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”), as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”) Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”) and Schneider, S., Agilent Technologies, Application Note- Combining small-scale purification and analysis of monoclonal antibodies on one instrument., 2017, pp. 1-8, retrieved from https://www.agilent.com/cs/library/applications/5991-1195EN.pdf?srsltid=AfmBOoqoreIJLM3sbHFheiUNqV0mfdidD3WzrIsZOhfMiYItGCLqoS5n on 11/21/2025 (herein after “Schneider”) as applied to claim 1, and in further view of Batts J.W., The column. 2014, vol. 10, issue 18, pp. 7-10, retrieved from https://www.chromatographyonline.com/view/hplc-systems-zones on 08/10/2024 (herein after “Batts”); have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 1 and 14-16 has been maintained.
New Rejections
Claim Rejections - 35 USC § 112
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.
1. Claim 6 is 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 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, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
In the instant case, claim 6 was amended (cf. amendment filed 07/24/2024) to include an additional step that further comprises (D) removing contaminants that have molecular weight less than the molecular weight of the complex. Applicants stated in their remarks that “the amendments do not introduce new matter” (see pg. 5, Remarks filed on 02/27/2026). However, after extensively reviewing the instant specification, it was determined that the recitation drawn to removing contaminants that have molecular weight less than the molecular weight of the complex is not supported by the instant specification.
Additionally, the instant specification describes the claimed polypeptide separation method in three steps, as described para[0009], pp. 2-3 of the instant specification:
step A: a step of mixing the polypeptide and a ligand in a liquid to form a complex of the polypeptide and the ligand and to obtain a liquid containing the complex;
step B: a step of filtering the liquid containing the complex obtained in the step A;
step C: a step of further separating the complex separated in the step B into the polypeptide and the ligand.
As such, the one and only step in the instantly claimed separation method that describes an additional measure or furthering step is step C. Therefore, the claim limitation drawn to removing contaminants that have molecular weight less than the molecular weight of the complex is not supported by the instant specification and thus it is new matter.
The specification is void of evidence that would clearly support the newly added step D. The specification does not make reference to contaminants that have molecular weight less than the molecular weight of the complex. Instead, the specification recites that with the step B, the liquid containing the complex of the polypeptide and the ligand can be separated into the complex of the polypeptide and the ligand and an impurity (see instant specification, pg. 9, para[0030], lines 14-15). Furthermore, the instant specification recites that the term “impurity” refers to a by-product produced in the process of producing a polypeptide (see pg. 6, para[0019], lines 9-10). As such, the impurity is inherent to the production process of the monoclonal antibody, while a contaminant is not inherent to the production process, thus it is an external substance present in the liquid composition.
Additionally, since words of a claim must be given their “plain meaning” unless such meaning is inconsistent with the specification, as stated in MPEP 2111.01(I). The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. Saicm Knowledge teaches that “contaminants” may enter the products, i.e. mixtures or articles, at any stage of the life cycle and potential sources of contaminants are: (unintended) reactions of substances, e.g. if a material is processed under very hot conditions; residues in processing equipment, e.g. if a plastic compound is extruded, remnants of the material that has been extruded in a previous manufacturing cycle may reside in the machines and be transferred to the product; or processing auxiliaries may remain in the product, such as solvents, lubricants etc. (see Guidance Impurities and Contaminants, retrieved from https://saicmknowledge.org/sites/default/files/inline-files/1_9_guidance_impurities_Review_corrected%20Oct%202022.pdf on 04/28/2026).
Therefore, the Examiner is interpreting the scope of removing contaminants as recited in amended claim 6, as removing substance(s) external to the liquid composition (i.e., substance(s) that are not a by-product produced in the process of producing a polypeptide) and that have a molecular weight less than the molecular weight of the complex.
Examination of the instant support shows that the envisioned monoclonal antibody separation method comprises the formation of a complex of the polypeptide and the ligand; and a filtration step which separates the formed complex from an impurity (see instant specification, pg. 5, para[0015]). The formation of the complex is preferred since the size difference from the impurity is larger and filtration conditions can be relaxed (see instant specification, pg. 5, para[0015]). However, the claimed genus of “impurities” is not limited to contaminants or to external contaminants. Pursuant to MPEP 2163.03(V), [a]n original claim may lack written description support when . . . (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002). Thus, the instant specification describes that the complex of the polypeptide and the ligand can be separated into the complex of the polypeptide and the ligand and an impurity. However, the instantly claimed genus encompassing any impurity has not been adequately supported; therefore, the claimed separation method comprising (D) removing contaminants that have molecular weight less than the molecular weight of the complex is not expressly described.
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.
2. Claims 1-3, 5-8, 10 and 13 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.
Amended claim 1 is drawn to a monoclonal antibody separation method comprising: […] (B) mixing the liquid composition and forming a plurality of complexes comprising the monoclonal antibody and the at least one ligand, wherein at least 70% of the plurality of complexes comprise two or more monoclonal antibody molecules and one ligand molecule, and wherein no more than 30% of the plurality of complexes comprise one monoclonal antibody molecule and one ligand molecule. However, it is not clear whether the plurality of complexes formed are all identical (i.e., comprise the same ligand) or whether the plurality of complexes formed comprise a variety of complexes, wherein the ligand molecule varies (i.e., complexes formed by Protein A, Protein G and Protein L).
As such, an ordinary skilled artisan would not be able to ascertain the metes and bounds of the claimed invention with respect to the plurality of complexes comprising two or more monoclonal antibody molecules and one ligand molecule, nor with respect to the plurality of complexes that comprise one monoclonal antibody and one ligand molecule. Since it has not been clearly established whether one or more ligands are present in the provided liquid composition; the plurality of complexes that form after the mixing step encompass complexes formed by one or more ligands.
Additionally, the newly added limitation recited in (C) filtering the liquid composition to isolate the plurality of complexes, renders the claim indefinite. An ordinary skilled artisan would not be able to determine which plurality of complexes will be isolated by the filtering step; since the liquid composition comprises a plurality of complexes (i.e., complexes formed by protein A, protein G, protein L; complexes formed by two or more monoclonal antibody molecules and one ligand molecule; and complexes formed by one monoclonal antibody molecule and one ligand molecule).
Accordingly, claim 1 and dependent claims 2-3, 5-8, 10 and 13 are indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
3. Claims 13 is 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 13 recites the limitation "the liquid composition produced in (B)" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Instant claim 13 is fails to establish whether the liquid composition produced in (B) is the same as the liquid composition provide in (A) as recited in parent claim 1. An ordinary skilled artisan would not be able to determine the metes and bounds of the claimed invention with respect to the claimed liquid composition because parent claim 1 does not include any steps drawn to producing a liquid composition, instead a liquid composition is provided in (A) and mixed in (B). Therefore, the newly added limitations to instant claim 13 render the claim indefinite because it fails to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Maintained/Modified Rejections in Light of Amendments
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
4. Claims 1-2, 4 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”) as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”), in view of Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”).
Regarding claim 1, Reis claims a method for separating a first species of interest from a second species of interest in a free solution mixture comprising said first and second species of interest, said first and second species of interest being different, said method comprising: contacting said free solution mixture with a soluble small molecular weight ligand that interacts with said first species of interest, wherein the molecular weight of said ligand is smaller than the molecular weight of said first species of interest and wherein said interaction forms a first species of interest/ligand complex (see pg. 8, right column, claim 1). Thereby corresponding to a separation method comprising providing a liquid composition, as recited in (A); and also corresponding to mixing the liquid composition and forming a plurality of complexes, as recited in (B) of instant claim 1.
Additionally, Reis’ claim 17 teaches that wherein said step of separating (i.e., a first species of interest from a second species of interest) is accomplished by membrane filtration (See Reis, pg. 9, right column, claim 17), and the membrane filtration is high performance tangential flow filtration, ultrafiltration, or reverse osmosis or microfiltration (See Reis, pg. 9, right column, claims 18-20). Thereby corresponding to (C) filtering the liquid composition to isolate the plurality of complexes, as recited in instant claim 1. Reis specific Example 1, teaches the molecular separation of Recombinant Humanized IgG (rhuIgG) from a Bovine Serum albumin impurity using a soluble protein A ligand (See Reis, pg. 7, para0068]). As evidenced by Constantino, recombinant humanized immunoglobulin G (rhuIgG) is monoclonal (See Costantino, pg. 122, left column, paragraph 1). As such, the teachings of Reis read on wherein the liquid composition comprises a monoclonal antibody and at least one ligand selected from Protein A, Protein G and Protein L, as recited in (A) of instant claim 1.
Reis teaches Example I, which recites the molecular separation of recombinant humanized IgG (rhuIgG) from a Bovine Serum Albumin impurity using a soluble protein A ligand (See Reis, pg. 7, para[0068]). In Reis’ example, the complex containing 0.8 mg/ml of rhuIgG and 0.2 mg/ml of rPrA (i.e., recombinant protein A) was formed by combining and diluting stock solutions in the mobile phase buffer (i.e., 0.025 M NaCl, 0.025 M Tris base, 0.005 M EDTA, pH 7.1±0.1) (See Reis, pg. 7, left column, para[0070). It is noted that Reis teaches a ratio of 4:1 (i.e., 0.8 mg/ml of rhuIgG:0.2 mg/ml of rPrA). However, Reis does not expressly indicate wherein the liquid composition comprises at least 2.1 moles of a monoclonal antibody and 1 mole of at least one ligand for the monoclonal antibody.
Bilitewski teaches that protein A is a cell surface protein of Staphylococcus aureus, which is capable of binding the Fc domain of immunoglobulins, especially of IgGs, from different species, for example human, rabbit, pig or monkey (See Bilitewski, pg. 240, left column, paragraph 6). Protein A consists of a single polypeptide chain with a molecular weight of approx. 40–60 kDa and contains 4–5 IgG binding domains (See Bilitewski, pg. 240, left column, paragraph 6). Bilitewski also teaches that each protein A molecule can bind at least 2 IgG molecules simultaneously (See Bilitewski, pg. 240, left column, paragraph 6).
Bilitewski expressly suggests that protein A as a ligand can bind at least 2 IgGs simultaneously. Therefore, the molar ratio of monoclonal antibody to ligand is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal molar ratio of monoclonal antibody to ligand needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the molar ratio of monoclonal antibody to ligand as taught by Reis in light of Bilitewski, to form a complex between the protein of interest and the ligand, thereby resulting in the separation of the species of interest/ligand complex. An ordinary skilled artisan would have been able to utilize the teachings of Bilitewski to determine the molar ratio of monoclonal antibody to ligand given that protein A is a multi-ionic molecule and can bind at least 2 IgG molecules. Therefore, one of ordinary skill in the art would be able to optimize the molar ratio of 2.1:1 as recited in instant claim 1 with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the ratio of polypeptide to ligand in the separation method would have been obvious before the effective filing date of Applicant's invention.
With respect to (B) wherein at least 70% of the plurality of complexes comprise two or more monoclonal antibody molecules and one ligand molecule, and wherein no more than 30% of the plurality of complexes comprise one monoclonal antibody molecule and one ligand molecule, as recited in instant claim 1.
The MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the Examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, Reis teaches that the ligand (i.e., protein A) is a multi-ionic molecule (See Reis, pg. 9, left column, claim 7); and Bilitewski teaches that each protein A molecule can bind at least 2 IgG molecules simultaneously (See Bilitewski, pg. 240, left column, paragraph 6). The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not at least 70% of the plurality of complexes comprise two or more monoclonal antibody molecules and one ligand molecule, and wherein no more than 30% of the plurality of complexes comprise one monoclonal antibody molecule and one ligand molecule. The cited art taken as a whole demonstrates a reasonable probability for two molecules of the monoclonal antibody to bind to each protein A molecule is either identical or sufficiently similar to the claimed abundance ratio of complexes of at least two molecules of the monoclonal antibody with one molecule of the ligand is 70% or more, and the abundance ratio of complexes of a single molecule of the monoclonal antibody with a single molecule of the ligand is 30% or less, and that whatever differences exists are not patentably significant. Therefore, with the showing of the references, the burden of establishing novelty or non-obviousness by objective evidence is shifted to the Applicants.
As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow the teachings of Reis for separating a first species of interest from a second species of interest in a free solution mixture by contacting the solution mixture with a soluble small molecular weight ligand that interacts with said first species of interest forming a first species of interest/ligand complex. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because Reis’ soluble small molecular weight ligand is protein A, and first species of interest is Recombinant Humanized IgG (rhuIgG) from a Bovine Serum albumin impurity. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that protein A contains 4-5 IgG binding domains and can bind at least 2 IgG molecules simultaneously as taught by Bilitewski. Therefore, the molecular separation of Recombinant Humanized IgG (rhuIgG) from a Bovine Serum albumin impurity using a soluble protein A ligand would support a method for separating a species of interest from other different species present in a free solution mixture by constituting some teaching suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claim 2, Reis teaches that monoclonal antibodies directed against a protein of interest may be made using the hybridoma method (see Reis, pg. 5, para[0054]). The hybridoma cells thus prepared may then be seeded and grown in a suitable culture medium (see Reis, para[0055]). The culture medium in which hybridoma cells are grown is then assayed for the production of monoclonal antibodies directed against the protein of interest (see Reis, para[0057]). Thereby, corresponding to wherein the provided liquid composition in (A) is a cell culture media.
Regarding claim 4, Reis’s Example I is drawn to molecular separation of recombinant humanized IgG from a Bovine Serum Albumin Impurity using a soluble Protein A ligand. (See Reis, pg. 7, left column, para[0068]). Thereby corresponding to wherein the at least one ligand is Protein A.
Regarding claim 13, as previously discussed, Reis teaches that the ligand (i.e., protein A) is a multi-ionic molecule (See Reis, pg. 9, left column, claim 7). Bilitewski teaches that each protein A molecule can bind at least 2 IgG molecules simultaneously (See Bilitewski, pg. 240, left column, paragraph 6).
The MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the Examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, Reis teaches that the ligand (i.e., protein A) is a multi-ionic molecule (See Reis, pg. 9, left column, claim 7); and Bilitewski teaches that each protein A molecule can bind at least 2 IgG molecules simultaneously (See Bilitewski, pg. 240, left column, paragraph 6). The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not the liquid composition produced in (B) comprises no more than 5% of monoclonal antibody molecules not complexed with the ligand. The cited art taken as a whole demonstrates a reasonable probability for the mixed liquid composition to comprise no more than 5% of monoclonal antibody molecules not complex with the ligand, and that that whatever differences exists are not patentably significant. Therefore, with the showing of the references, the burden of establishing novelty or non-obviousness by objective evidence is shifted to the Applicants.
5. Claims 1 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”) as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”) and Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”) as applied to claim 1, and further in view of JP2009221137 A, published on October 1st 2009, Machine translation (cited in the IDS filed on 12/21/2020) (herein after “Yamaguchi”) and JP2009221137A-Espacenet Machine Translation (herein after “Yamaguchi Espacenet MT”), as applied to claim 5 herewith.
Regarding claim 1, please see discussion of Reis and Bilitewski above.
Regarding claim 5, Reis teaches membrane filtration of the free solution mixture(see Reis, pg. 9, right column, claim 17), thereby corresponding to wherein the filtering in (C) comprises passing the liquid composition through a membrane. However, Reis does not expressly teach wherein the membrane has a fractional molecular weight ranges from 10,000 to 250,000.
Yamaguchi teaches a method of separating a target biological component and an impurity biological component by cross-flow filtration using an ultrafiltration membrane having a fractional molecular weight of 0.5 to 2 times the average molecular weight of the impurity biological component (See Espacenet MT, pg. 2, paragraph 5). Yamaguchi’s claim 9 teaches a method of purifying a mixed solution comprising 2 or more impurity biological components, wherein the method of claim 1 (i.e., cross-flow filtration using an ultrafiltration membrane) is performed 1 or more times to separate the target biological component and the impurity biological component (See Yamaguchi, Machine Translation, claim 9). Yamaguchi teaches that a membrane having a desired cut-off molecular weight can be manufactured, and, without being limited thereto, a hydrophilic sulfone polymer membrane, for example, can be used without any limitation (see Yamaguchi, Machine Translation, para[0019]). In addition, from the viewpoint of compatibility with an electrostatic property of an object to be separated, a chemical structure such as an amino group, a monoalkyl amino group, a dialkylamino group, a carboxyl group, a sulfonyl group, and a sulfonic acid group may be introduced as required (See Yamaguchi, Machine translation, para[0024]). The weight average molecular weight of the sulfone polymer according to Yamaguchi’s invention may be 5000 to 1,000,000. It is preferably from 10000 to 500,000, more preferably from 2 to 300,000 (See Yamaguchi, Machine Translation, para[0024]). Within this range, sufficient strength and film formability can be obtained (See Yamaguchi, Machine Translation, para[0024]). Thus Yamaguchi suggest using a sulfone polymer manufactured membrane compatible with an electrostatic property of the object to be separated and having a desired cut-off molecular weight that is preferably 2 to 300,000 in order to separate biological components larger than 1000 kDa, thereby constituting where the membrane for use in the filtration step is 10,000 to 250,000 as recited in instant claim 5.
Additionally and/or alternatively, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed fractional molecular weight of a membrane range would have been obvious to one of ordinary skill in the art since the prior art range (i.e., may be 5000 to 1,000,000; preferably from 10000 to 500,000; and more preferably from 2 to 300,000) lies within the claimed fractional molecular weight of a membrane range (i.e., 10,000 to 250,000). As such, the teachings of Yamaguchi satisfy the claim limitations as recited in instant claim 5.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Reis and use a sulfone polymer membrane with an average fractional molecular weight of 2 to 300,000 as taught by Yamaguchi to filter the liquid containing the complex. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because a sulfone polymer membrane was known to be used in separation methods of biological components larger than 1000 kDa, and because a sulfone polymer membrane was known to have sufficient strength and film formability at weight molecular ranges varying from 5000 up to 1,000.000 as taught by Yamaguchi. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that the rhuIgG and rPrA complex of Reis was separated via membrane filtration and once the complex was disassociated the individual parts were further separated by filtration as well. Therefore, using a sulfone polymer membrane with an average fractional molecular weight of 2 to 300,000 as the membrane filtration in order to remove impurities, would support a method for separating a species of interest from other different species present in a free solution mixture by constituting some teaching suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
6. Claims 1 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”) as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”); in view of Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”), as applied to claim 1, and further in view of Merk Millipore., Sample Preparation Product Guide, 2014. pp. 1-250, Lit No. CA5833ENEU BS-GEN-13-08849, retrieved from https://www.postnova.com/images/pdf/Postnova_Catalog_MerckMillipore_SamplePreparation.pdf on 04/28/2026 (herein after “Merk”).
Regarding claim 1, please see discussion of Reis and Bilitewski.
Regarding claim 6, Reis’ method further comprises the step of disassociating said first species of interest/ligand complex into its individual components, wherein disassociation occurs after said step of separating (see Reis, pg. 9, claim 21). As previously mentioned, Reis’ separating step is accomplished by membrane filtration such as ultrafiltration, reverse osmosis or microfiltration (see Reis, pg. 9, claims 17 and 20). Thereby corresponding to further comprising disassociating the complexes to provide the separated monoclonal antibody.
However Reis does not expressly teach (D) removing contaminants that have molecular weight less than the molecular weight of the complex, as recited in instant claim 6.
Merk teaches that ultrafiltration is the process of separating extremely small particles and dissolved molecules rom fluids and that the process can only separate molecules which differ by at least an order of magnitude in size (see Merk, pg. 5, middle column). Merk adds that materials larger than the pore size rating are retained by the filter and can be concentrated or separated from low molecular weight contaminants (see Merk, pg. 5, middle column); thereby corresponding to removing contaminants that have molecular weight less than the molecular weight of the complex, as recited in (D) of instant claim 6. Merk also teaches that ultrafiltration is far gentler to solutes than processes such as precipitation, and it is more efficient because it can simultaneously concentrate and desalt solutes; it does not require a phase change, which often denatures labile species, such as proteins, thus it is the ideal method for preparing protein samples (see Merk, pg. 5, right column). As such, the combined teachings of Reis and Merk read on the claim limitations recited in instant claim 6.
An ordinary skilled artisan would have been motivated with reasonable expectation of success before the effective filing date of the claimed invention to follow the teachings of Reis and separate a first species of interest from a second species of interest in a free solution mixture by membrane filtration, wherein the membrane filtration is ultrafiltration; and to further dissociate said first species of interest/ligand complex into its individual components after the ultrafiltration step, in order to arrive at the claimed method. One of ordinary skilled in the art would have been motivated to do so because it was known that ultrafiltration membranes retain and concentrate materials larger than the pore size rating thus separating the materials from low molecular weight contaminants, as taught by Merk. One of ordinary skilled in the art would had had a reasonable expectation of success given that ultrafiltration is the ideal method for preparing protein samples since it is far gentler to solutes than processes such as precipitation; given that it is more efficient because it can simultaneously concentrate and desalt solutes; and given that it does not require a phase change, which often denatures labile species, such as proteins, as taught by Merk. Therefore, the separation method of a first species of interest from a second species of interest as taught by Reis would support the instantly claimed monoclonal antibody separation method by constituting some teaching suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, and/or the use of known technique to improve similar devices (methods, or products) in the same way, pursuant to KSR.
Regarding claim 7, Reis teaches that final purification of the rhulgG product was achieved by separation of the individual protein and ligand molecules using HPLC-SEC (see Reis, pg. 8, para[0083]), thereby corresponding to further comprising purifying the separated monoclonal antibody by liquid chromatography.
7. Claims 1 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”) as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”); in view of Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”), as applied to claim 1, and further in view of Schneider, S., Agilent Technologies, Application Note- Combining small-scale purification and analysis of monoclonal antibodies on one instrument., 2017, pp. 1-8, retrieved from https://www.agilent.com/cs/library/applications/5991-1195EN.pdf?srsltid=AfmBOoqoreIJLM3sbHFheiUNqV0mfdidD3WzrIsZOhfMiYItGCLqoS5n on 11/21/2025 (herein after “Schneider”), as applied to claim 8.
Regarding claim 1, please see discussion of Reis and Bilitewski.
Regarding claim 8, Reis teaches that final purification of the rhulgG product was achieved by separation of the individual protein and ligand molecules using HPLC-SEC (see Reis, pg. 8, para[0083]). However, Reis does not expressly teach wherein the liquid chromatography is ion exchange chromatography.
Schneider teaches purification of a monoclonal antibody from a cell lysate and the subsequent analysis on a single instrument, the Agilent 1260 Infinity Bio-inert Quaternary LC System (see pg. 1, Abstract). Schneider teaches a two-step purification procedure for monoclonal antibodies (mAb) out of cell lysate using Protein A affinity chromatography (i.e., first step) followed by a size exclusion polishing step (see pg. 2, left column, paragraph 2). Subsequently, the purified mAb fraction was, on an analytical scale, identified and quantified with Protein A affinity chromatography and the charge variants were characterized with ion exchange chromatography (IEX) (see pg. 2, left column, paragraph 2). Due to the separation technique of the SEC (size exclusion chromatography) polishing step, the fractionated samples were diluted to a large extent (see pg. 4, left column). Before analytical chromatography could be applied to the sample, a concentration step was carried out by ultrafiltration using Amicon Ultra Centrifugal Filters 30K (see pg. 4, left and center columns). Schneider adds that by using a preparative affinity column coated with protein A, the mAb was captured and successfully separated from the E. coli cell lysate with an enormous protein content of over 100 mg/mL (see pg. 5, left column, second paragraph). For higher levels of purity, additional purification steps can be added prior to the SEC polishing such as IEX (ion exchange chromatography) (see pg. 2, middle column, paragraph 1). As such, the teachings of Schneider are suggestive of the claim limitations as recited in instant claim 8.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Reis with the teachings of Schneider in order to arrive at the claimed separation method wherein the separation of the monoclonal antibody by liquid chromatography is ion exchange chromatography. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because Schneider’s purification method of a monoclonal antibody is performed in two steps, employs protein A and it yields an enormous protein content of over 100 mg/mL. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that Schneider’s two step purification method can include additional purification steps such as IEX (ion exchange chromatography), prior to the second step (i.e., SEC polishing/size exclusion chromatography). Therefore, two step purification method of a monoclonal antibody from a cell lysate where ion exchange chromatography, as an additional purification step, would support a method for separating a species of interest from other different species present in a free solution mixture by constituting some teaching suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the use of known technique to improve similar devices (methods, or products) in the same way, pursuant to KSR.
8. Claims 1 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”) as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”); in view of Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”), as applied to claim 1, and further in view of , and in further view of Batts J.W., The column. 2014, vol. 10, issue 18, pp. 7-10, retrieved from https://www.chromatographyonline.com/view/hplc-systems-zones on 08/10/2024 (herein after “Batts”), as applied to claim 10 herewith.
Regarding claim 1, please see discussion of Reis and Bilitewski.
Regarding claim 10, Batts teaches the basic and essential components of a chromatography system (See Batts, pg. 1, abstract). It is essential to fully understand how a system works and what accessories (for example, tubing, fitting, and filters) are needed for proper system operation (See Batts, pg. 1, abstract). Understanding what these basic components are and what each component is required to do is critical to having a more thorough understanding of how liquid chromatography (LC) systems work overall and subsequently how to best accessorize the fluidic pathway (See Batts, pg. 1, paragraph 2). Apart from the PC (or data collection device), a basic HPLC system is comprised of seven primary components, six of which are required and one that has become so essential to proper system operation that it is built into most new systems available today (See Batts, pg. 2, paragraph 2).
With respect to wherein the monoclonal antibody purification device comprises a supply tank, a diluent supply tank, a filter, and a detector:
Batts teaches Component # 1 – The Solvent Reservoir: As the name indicates, the solvent reservoir serves as a storage tank for the reagents that will be used as the mobile phase of the system (See Batts, pg. 2, paragraph 3). Batts’Component #5 – The Column: Most columns are simple tubes that have been densely packed with innumerable spherical beads – each typically 5-μm or less in diameter – and the beads are most often surface-modified to alter the chemical environment inside the column (See Batts, pg. 3, paragraph 3). Because the material packed into the column tubes is bracketed by a filtration disc (or a "frit") on both the inlet and outlet side of the column, the packing material remains in place, even as the mobile phase passes through it (See Batts, pg. 3, paragraph 3). Therefore, the material packed inside the column tube is typically referred to as the stationary phase (See Batts, pg. 3, paragraph 3). The full column assembly is often referred to as the heart of the LC system, for it is within this component that the separation of the sample into its constituent parts occurs (See Batts, pg. 3, paragraph 3). It is the resistance to fluid flow through the densely packed stationary phase of the column that causes the majority of the high pressure for which HPLC is most well-known (See Batts, pg. 3, paragraph 3).
Batts teaches Component #6 – The Detector: As its name would imply, the detector is responsible for "detecting" the sample components that leave the column (See Batts, pg. 4, paragraph 1). Batts teaches Component #7 – The Waste Reservoir: The waste reservoir is most typically a large glass or chemically resistant polymer container into which the mobile phase and sample components flow after separation and detection has taken place, keeping the chemicals stored until they can be safely disposed of (See Batts, pg. 4, paragraph 2). Please note that “reservoir” is being interpreted as a storage tank (i.e., a part of an apparatus in which a liquid is held or stored).
Additionally, with respect to the uses of the monoclonal antibody purification device, recited in claim 10 (i.e., (B) mixing the liquid composition and forming a plurality of complexes; and (C) filtering the liquid composition to isolate the plurality of complexes), the discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02. Moreover, “[t]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. As such, claim 10 can be deemed to recite an intended use of the claimed monoclonal antibody purification device. A recitation of an intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim limitation. Accordingly, since Batts teaches the basic and essential components of traditional high performance liquid chromatography (HPLC) which include the solvent reservoir, a column (i.e., filter), a detector and the waste reservoir encompassed by the presently claimed invention, the intended uses of the monoclonal antibody purification device are also taught.
Similarly, since claim 10 can be deemed to recite an intended use of the claimed supply tank of a product to be purified and the diluent tank. A recitation of an intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim limitation. Accordingly, since Batts discloses the basic and essential components of traditional high performance liquid chromatography (HPLC) which include the solvent reservoir and the waste reservoir (i.e., tanks or parts of an apparatus in which liquid is held or stored) encompassed by the presently claimed invention, the intended uses of the supply tank of a product to be purified and the diluent supply tank are also taught.
9. Claims 1 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over US 2003/0121854 A1, published on July 3rd 2003 (herein after “Reis”), as evidenced by Costantino et al., Pharmaceutical Sciences. 1997, vol 3 pp. 121-128 (herein after “Costantino”), in view of Bilitewski, U., Analytica Chimica Acta. 2006, 568, pp. 232-247 (herein after “Bilitewski”) as applied to claim 1, and further in view of US 2017/0145051 A1, Pub Date: May 25, 2015 (cited in the IDS filed on 12/21/2020) (herein after “Momiyama”), as applied to claims 15-16 herewith.
Regarding claim 1, please see discussion of Reis and Bilitewski.
Reis does not expressly teach wherein the at least one ligand is Protein G, nor wherein the at least one ligand is protein L, as recited in claims 15 and 16 respectively.
Momiyama is in the field of affinity chromatography and teaches an affinity chromatography carrier that suppresses nonspecific adsorption of impurities, suppresses a decrease in dynamic binding capacity due to long-term storage, and has high storage stability (see Abstract). Momiyama also teaches that the affinity chromatography carrier reduces a residual amount of epoxy groups on the surface, and also has high hydrophilicity due to the ring opened epoxy groups (see pg. 1, para[0023]). Therefore, it is possible to improve an ability to remove nonspecifically adsorbing impurities, such as host cell proteins (HCPs) and DNA (see pg. 1, para[0024]). Momiyama’s affinity chromatography carrier also allows the ligand to maintain high activity (see pg. 1, para[0025]). Additionally, Momiyama teaches that the ligand may be of any type having a suitable level of affinity for target materials (see pg. 7, para[0118]). Examples of the ligand include, but are not limited to, proteins such as protein A, protein G, protein L (see pg. 7, para[0118]). The ligands may be used as they are, or their recombinant forms or their fragments obtained by enzyme treatment or the like may also be used. The ligand bay also be an artificially synthesized peptide or peptide derivative (see pg. 7, para[0118]). Momiyama also teaches Test Example 5, where a CHO cell culture supernatant containing a monoclonal antibody, Trastuzumab was allowed to flow at a rate of 1 mL/minute with a load of about 23 mg antibody/mL carrier through the column (see pg. 11, para[0174). The monoclonal antibody captured in the column was eluded, and eluted fractions with Abs. 280>100 mAu were collected (see pg. 11, para[0176]). The results shown in Table 1, indicate the amount of coupled protein A, where it can be seen that 83mg/g of protein A was coupled to the monoclonal antibody and had a high stability of 94% (see pg. 11, Table 1, first entry). Momiyama also teaches that the amount of host cell proteins (HCP) per unit amount of antibody was calculated by dividing the HCP concentration by the antibody concentration (see pg. 11, Table 1, first entry).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Reis with the teachings of Momiyama and incorporate an affinity chromatography carrier that has a ligand with a suitable level of affinity for target materials, such as protein A, protein G, and/or protein L; in order to arrive at the claimed monoclonal antibody separation method. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because Momiyama’s affinity chromatography carrier allows the ligand to maintain high activity and the affinity chromatography carrier suppresses nonspecific adsorption of impurities, suppresses a decrease in dynamic binding capacity due to long-term storage, and has high storage stability. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that when 23mg of antibody/mL carrier where allowed to flow through column, the amount of couple protein A was 83mg/g. Additionally, an ordinary skilled artisan would have been able to utilize the teachings of Bilitewski to determine the molar ratio of monoclonal antibody to ligand given that protein A is a multi-ionic molecule and can bind at least 2 IgG molecules. Therefore, the affinity chromatography carrier that has a ligand with a suitable level of affinity for target materials, such as protein A, protein G, and/or protein L would support a method for separating a species of interest from other different species present in a free solution mixture by constituting some teaching suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 U.S.C 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references discussed above.
Response to Arguments
Applicants’ arguments filed on 02/27/2026, with respect to the 35 U.S.C. 103 rejections to claims 1-2, 4-10, 13 and 14-15, are found unpersuasive.
Applicants assert that the claimed method as recited in amended claim 1, is neither disclosed nor suggested by the cited references considered alone or in all possible combinations (see Remarks, filed 02/27/2026, pg. 6, second to last paragraph). Applicants add that even if an ordinary skilled artisan would have considered the cited references, the person would not have had any reasonable expectation of success (see Remarks, filed 02/27/2026, pg. 10, second paragraph). These arguments are found unpersuasive.
Applicants are respectfully reminded that the rejections supra are based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. Additionally, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In the instant case, an ordinary skilled artisan would have been motivated with reasonable expectation of success to achieve the claimed invention before the effective filing date because monoclonal separation methods comprising a ligand such as Protein A, protein G or Protein L and a monoclonal antibody were known; and because it was also known that a ligand such as protein Ais a multi-ionic molecule and can bind at least 2 IgG molecules. Therefore, contrary to Applicants’ arguments, an ordinary skilled artisan after reading the cited prior art would have found motivation to arrive at the claimed invention based on what was already known and based in the knowledge generally available to one of ordinary skill in the art. As such, an ordinary skilled artisan would have been able to optimize the ratio of monoclonal antibody to ligand in order to achieve the claimed plurality of complexes wherein at least 70% of the complexes formed comprise two or more monoclonal antibody molecules and one ligand molecule, and wherein no more than 30% of the plurality of complexes comprise one monoclonal antibody molecule and one ligand molecule.
Additionally, obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). See MPEP 2143.02(II).
Since Applicants do not provide any evidence that at least two molecules of monoclonal antibody do not bind to a ligand such as protein A, then the instantly claimed method remains obvious. The cited prior art demonstrates that a ligand such as protein A can bind at least 2 IgG molecules therefore there is at least some degree of predictability in achieving the claimed invention wherein at least 70% of the plurality of complexes comprise two or more monoclonal antibody molecules and one ligand molecule and wherein no more than 30% of the plurality of complexes comprise one monoclonal antibody molecule and one ligand molecule.
With respect to the highly relevant data reported in Tables 1 and 2, and Applicants’ assertion that complexes falling within the requirements of amended claim 1 are produced by mixing a molar ratio of monoclonal antibody to ligand of at least 2.1 M to 1M (see Remarks, filed 02/27/2026, pp. 8-9). These arguments are found unpersuasive.
Pursuant to MPEP 716.02(c) II, expected beneficial results are evidence of obviousness. Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
In the instant case, since the prior art cited in the 35 U.S.C 103 rejection above renders the claimed invention obvious, including the amendments to instant claim 1, the highly relevant data reported in Tables 1 and 2 of the instant specification, would have been expected, and thus the highly relevant data is evidence of obviousness.
Furthermore, pursuant under MPEP 716.02(d), whether the unexpected results are the results of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” With respect to amended claim 1, the scope of the claimed method comprises providing a liquid composition comprising at least 2.1 moles of a monoclonal antibody and at least 1 mole of at least one ligand […] wherein at least 70% of the plurality of complexes comprise two or more monoclonal antibody molecules and one ligand molecule, and wherein no more than 30% of the plurality of complexes comprise one monoclonal antibody molecule and one ligand molecule.
Thus the scope of amended claim 1 encompasses at least 2.1 moles of the monoclonal antibody, at least 1 mole of the ligand, at least 70% of complexes formed by 2:1 monoclonal antibody to ligand; and at most 30% of complexes formed by 1:1 monoclonal antibody to ligand.
Contrary to Applicants argument, the information depicted in Table 1, does not demonstrate how to attain the claimed abundance ratios required by amended claim 1. In particular, Applicants attest that the conditions of Reference Examples 1-5 meet the requirements of amended claim 1, while those of Reference Examples 6-9 do not (see Remarks, filed 02/27/2026, pg. 9, second paragraph).
However, upon reviewing the evidence provided in Table 1 and Table 2 (see instant specification pp. 17-18), it is evident that if an ordinary skilled artisan were to replicate the conditions of Reference Examples 1-5, the abundance ratio of complexes comprising 2:1 monoclonal antibody to ligand would not be at least 70%. Thus, in order for an ordinary skilled artisan to successfully obtain the claimed plurality of complexes (i.e., at least 70% comprising two or more monoclonal antibody molecules and one ligand molecule, and at most 30% comprising one monoclonal antibody and one ligand molecule); one of ordinary skill in the art would have to replicate the conditions in Reference Examples 8-9 (see instant specification, Tables 1-2, pp. 17-18). It is also noted that, in order to achieve the claimed invention, the ordinary skilled artisan would have to consider a third element which is not encompassed by the instant claims. Thus, other than the claimed 2.1 moles of monoclonal antibody and 1 mole of at least one ligand, the effect of the amount of phosphate buffer solution is a third parameter to be considered as part of the claimed separation method.
In other words, Reference Example 7, requires a molar ratio of 1.8:1 of polypeptide to ligand (see pg. 17, Table 1, Reference Example 7), in order to achieve an abundance ratio of 78.6% of two or more molecules of monoclonal antibody with one molecule of ligand, and a ratio 21.4 % of one molecule of monoclonal antibody with one molecule of ligand (see pg. 18, Table, Reference Example 7). However, the abundance ratio of 78.6% obtained with a monoclonal antibody to ligand ratio of 1.8:1 is not the same as the claimed 70% or more of complexes that would be obtained under the claimed parameters as recited in instant claim 1. The parameters recited in instant claim 1 (i.e., at least 2.1 moles mAb : 1 mole ligand), do not result in 70% abundance ratio of complexes formed by at least 2 molecules of mAb to 1 molecule of ligand.
Additionally, it is noted that the second percentage of claimed complexes formed (i.e., no more than 30% 1:1 mAb to ligand) is achieved under conditions that require a molar ratio of 1.6:1 mAb:ligand) (see pg. 18, Table 2, Reference Example 8). It is also noted that under the same conditions (i.e., 1.6:1 mAb:ligand) a first abundance ratio of 69.1% is obtained (see pg. 18, Table 2, Reference Example 8), which is a percentage that is closer to the claimed 70%. Therefore, the unexpected results of the claimed first abundance ratio of 70% or more of complexes formed by two or more molecules of mAb with one molecule of ligand are not commensurate in scope.
In response to Applicants’ argument with respect to impermissible hindsight (see Remarks, filed 02/27/2026, pg. 10), it is found unpersuasive.
It is the Examiner’s understanding that Applicant is suggesting that the Examiner’s position fails to establish a prima facie case of obviousness because the prior art does not lead an artisan to the instant invention. If Applicant means to suggest that the Examiner arrived at the instantly claimed invention via the use of improper hindsight, this is not persuasive because any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here, Applicant fails to identify a single aspect of the claimed invention that was not taught, disclosed, or suggested by the prior art relied upon by the Examiner.
Accordingly, the 35 U.S.C 103 rejection of claims 1-2, 4-8, 10, 13 and 15-16 has been maintained, as Applicants’ arguments are found unpersuasive.
Conclusion
No claims are allowed.
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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