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
Status of the Claims
1. Claims 1-27 are the original claims filed 3/21/2023. In the Preliminary Amendment of 8/7/2023, Claims 4, 6, 9, 11, 12, 15-17, 19, 20, 24, 25, and 27 are amended and claims 7-8, 13-14, 18, 22-23, and 26 are cancelled.
Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27 are pending.
Priority
2. USAN 18/124,096, filed 03/21/2023, is a Continuation of PCT/US2021/051047, filed 09/20/2021, PCT/US2021/051047 Claims Priority from Provisional Application 63/080,950, filed 09/21/2020. The priority date of 09/21/2020 is granted.
Information Disclosure Statement
3. AS of 1/26/2026, a total of two (2) IDS are filed: 0/29/2023; and 9/30/2025. The corresponding initialed and dated 1449 forms are considered and or record.
Objections
Specification
4. The disclosure is objected to because of the following informalities:
a) The use of the term Capto, Tris, Orion, UNIX, MEGALIGN, DNASTAR, BiTE, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The specification contains a typographical error at [0117]: “…a conductivity of about xxx mS/cm.”
Appropriate correction is required.
Claim Objections
5. Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27 are objected to because of the following informalities:
a) Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27 are objected to because of the phrase “capable of.” The phrase implies that some undefined structure and/or condition is what predicates whether the activity does or does not occur. Capacity and capability suggest that the activity may sometimes occur but not always, and what determines the degree or amount of the activity is indefinite by the use of the phrase.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claims 6 and 16 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.
a) Claim 6 contains the trademark/trade names CaptoTM Adhere resin and CaptoTM Adhere ImpRes resin. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name.
In the present case, the trademark/trade name CaptoTM Adhere resin is used to identify/describe a MMAEX resin (see [0204]), accordingly, the identification/description is indefinite.
In the present case, the trademark/trade name CaptoTM Adhere ImpRes resin is not defined in the specification. Cytiva the manufacturer describes the resin as “a multimodal chromatography resin”, “This multimodal, strong anion exchange resin supports effective mAb polishing in the second or third step of a purification scheme downstream of the protein A capture step.” Accordingly, the identification/description is indefinite.
b) Claim 16 recites the limitation "wherein the capture chromatography step and the multi-mode chromatography step are contiguous." There is insufficient antecedent basis for this limitation in the claim. Claim 16 depends from both claims 1 and 9 and neither of which recite a capture chromatography step.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
7. Claims 1-6, 9-12, 15-17, 19-21, 24-25, and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The method claims 1-6, 9-12, 15-17, 19-21, 24 relate to a method for the purification of generic CrossMab VH/VL constructs from light-chain mis-paired variants thereof by mixed mode chromatography using anion exchange and hydrophobic interaction resin in flow-through mode.
Claim 27 relates to an article of manufacture comprising a multispecific antibody purified by the method of claim 1.
A) The method invention is unlimited in scope for the nature and kind of multispecific antibodies that are capable of purification by the method steps. The claimed antibodies relate to all possible antibodies much less isotypes including different subtypes of IgG, IgA, IgM, IgE, etc., and having any light chain (kappa or lambda) with the only proviso being that the VH and VL domains are replaced or swapped with the other.
B) The method invention is incomplete for omitting essential elements, such omission amounting to a gap between the elements. The omitted elements are the buffer conditions such as ionic strength, pH, etc. that influence the chromatography of any given protein. For example, the influence of buffer types is predicated by the kind of chromatography (see abcam.com/en-us/knowledge-center/proteins-and-protein-analysis/fplc-protein-purification):
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Disclosure in the Specification
The specification does not disclose any structure for the actual multispecific antibody used as the single prototype in Example 1 and identified as anti-Antigen A/anti-Antigen B bispecific antibody (aAgA/aAgB). No sequences or a sequence listing are provided in the application for the structures envisioned by Applicants. No structure for the CrossMab VH/VL construct is provided by reference to a known antibody in order for the POSA to reconstruct the antibody much less reproduce the experiment. “aAgA/aAgB” has no art-known definition. No information is provided in the drawings on how to generate the antibody used and as shown in those data.
The specification discloses the buffer conditions used in the “High-Throughput Screening” of the aAgA/aAgB antibody (paired and mispaired variants) in Figure 3 using “high pH” (anion-exchange) and “high salt concentration” (hydrophobic binding) in mixed mode material where the mispaired LC is resin-bound. None of those conditions are described in the instant claimed method.
The specification discloses the buffer conditions used in the “Confirmatory Column Chromatography Run” of the aAgA/aAgB antibody (paired and mispaired variants) in Figure 4. None of those conditions are described in the instant claimed method.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
Prior art status of multi-mode chromatography for antibodies
Further in view of the insufficient information for the single aAgA/aAgB prototype described in the specification are the caveats of using multi-mode (mixed-mode) chromatography on just any antibody. The challenges for different antibody isotypes in multimode chromatography include the need for tailored purification strategies to address the unique properties and characterisics of each isotype. For instance, the structural similarities between monoclonal antibodies and bispecific antibodies require careful selection of chromatographic interactions and resins to ensure effective separation and purification. Additionally, the need for high selectivity and versatility in chromatography tools is crucial to overcome the challenges posed by the diverse structures of bsAbs. (Yoshikawa, iptonline.com/collections/ipt-spring-2025/overcoming-challenges-in-bispecific-antibody-production-with-mixed-mode-chromatography-and-scalable-purification-solutions-spring-2025).
Multimodal chromatography has emerged as a powerful method for the purification of therapeutic antibodies. However, process development of this separation technique remains challenging because of an intricate and molecule-specific interaction towards multimodal ligands, leading to time-consuming and costly experimental optimization. (Hess et al., J. Chromatography A, Volume 1718, 15 March 2024, 464706).
The POSA is not reasonably apprised of the full breadth and scope of the claimed method envisaged by Applicants where description of the actual multispecific antibody is not divulged nor are the detailed steps used in the practice of the purification for the single limited prototype of Example 1 much less the criticality of the order in which they are performed.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
8. Claim(s) 1-2, 6, 9, 11-12, 15-17, 19-21, 24-25 and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over von Hirschheydt et al (US 11945839; 2018-12-20).
The method claims 1-2, 6, 9, 11-12, 15-17, 19-21, 24-25 relate to a method for the purification of CrossMab VH/VL constructs from light-chain mis-paired variants thereof by mixed mode chromatography using anion exchange and hydrophobic interaction resin in flow-through mode. The claimed method is not limited by the order in which any steps are taken in the generic or dependent claims.
Claim 27 relates to an article of manufacture comprising a multispecific antibody purified by the method of claim 1.
As regards Claim 1, von Hirschheydt teaches a method for separating a multispecific CrossMab antibody from a mispaired variant thereof by using a hydrophobic interaction chromatography (HIC) medium (Claim 1) wherein the CrossMab antibody comprises (a) a first antigen binding region specifically binding a first antigen, wherein the first antigen binding region comprises the light chain and heavy chain of an antibody binding the first antigen, and (b) a second antigen binding region specifically binding a second antigen, wherein the second antigen binding region comprises the light chain and heavy chain of an antibody specifically binding a second antigen, wherein in the second antigen binding region the VL and VH domains are swapped or exchanged or replaced with each other, i.e., CrossMabVH/VL (Claim 7). The mispaired variant of the CrossMabVH/VL is a variant comprising one or more light chains that are paired with a non-complementary heavy chain (claim 18).
von Hirschheydt teaches “(93) In various embodiments, the sample comprising the multispecific CrossMab antibody and mispaired variants thereof may be partially purified. For example, the solution may have already been subjected to any of a variety of art recognized purification techniques, such as chromatography, e.g., ion exchange chromatography, mixed mode chromatography, and/or affinity chromatography, or filtration, e.g., depth filtration, nanofiltration, ultrafiltration and/or absolute filtration.
As regards Claim 2, von Hirschheydt teaches a functional group for phenyl in corresponding to the hydrophobic interaction chromatography (HIC) at
(19) The HIC medium may in some aspects be selected from the group consisting of Butyl Sepharose HP, Capto Butyl ImpRes, Capto Phenyl ImpRes (all available from GE Healthcare) and PPG-600M (available as “Toyopearl 600M” from Tosoh). In a particular aspect of the present invention, the HIC medium may be selected from the group consisting of Butyl Sepharose HP, Capto Butyl ImpRes and Capto Phenyl ImpRes or it may have the same selectivity as Butyl Sepharose HP, Capto Butyl ImpRes, Capto Phenyl ImpRes or (Toyopearl) PPG-600M.
As regards Claim 2, von Hirschheydt teaches a functional group for alkyl in corresponding to the hydrophobic interaction chromatography (HIC) at (137) HIC media are composed of ligands containing alkyl or aryl groups coupled to an inert matrix of spherical particles. The ligand and the degree of ligand substitution on a HIC matrix contribute to the selectivity and, in addition, to the hydrophobicity of the medium. Thus, the type of ligand and the nature of the target protein are highly significant parameters in determining the selectivity of a HIC medium. The most common hydrophobic ligands of HIC media fall into two groups depending on their interactions with the sample components. Straight alkyl chains including butyl-, octyl-, ether- and/or isopropyl-groups and aryl ligands including phenyl-groups. In the context of the present invention, the ligands of HIC media used include phenyl-, butyl-groups and/or polypropylene glycol (PPG)-groups. Preferred are phenyl- and butyl-groups.
As regards claim 6, von Hirschheydt teaches the use of Capto ImPres resins
(19) The HIC medium may in some aspects be selected from the group consisting of Butyl Sepharose HP, Capto Butyl ImpRes, Capto Phenyl ImpRes (all available from GE Healthcare) and PPG-600M (available as “Toyopearl 600M” from Tosoh). In a particular aspect of the present invention, the HIC medium may be selected from the group consisting of Butyl Sepharose HP, Capto Butyl ImpRes and Capto Phenyl ImpRes or it may have the same selectivity as Butyl Sepharose HP, Capto Butyl ImpRes, Capto Phenyl ImpRes or (Toyopearl) PPG-600M.
AS regards Claim 9, von Hirschheydt teaches the use of gradient elution
(101) The term “bind-and-elute mode” denotes a way to perform a HIC chromatography purification method. Herein a solution comprising the multispecific CrossMab antibody to be purified and mispaired variant(s) thereof is applied to a stationary phase, particularly a solid phase, whereby the multispecific CrossMab antibody and/or the mispaired variants thereof interact with the stationary phase and is retained thereon. Substances not of interest are removed with the flow-through or the supernatant, respectively. The multispecific CrossMab antibody is afterwards recovered from the stationary phase in a second step by applying an elution solution (typically a buffered solution), typically in a stepwise or linear gradient (or a combination thereof) such that the multispecific CrossMab elutes separately from the variant (more different variants) thereof.
AS regards claims 11-12, 15, von Hirschheydt teaches capture chromatography by way of the Fc region of the bispecific antibody using Protein A, G or A/G attached to agarose
(31) The presence of an Fc domain renders the bispecific antibody amenable to purification using Fe-binding moieties such as, but not limited to, Protein A, Protein G, and/or Protein A/G.
(107) Further examples of suitable purification steps include hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being the preferred purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human γ1, γ2, or γ4 heavy chains (Lindmark et al., J. Immunol. Meth. 62:1-13[1983]). Protein G is recommended for all mouse isotypes and for human γ3 (Guss et al., EMBO J. 5:15671575[1986]). The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available.
AS regards Claims 16-17, von Hirschheydt teaches the HIC step is performed after a Protein A step and is followed by a cation exchange step in a bind-and-elute mode and an anion exchange step in a flow-through mode (page 38, lines 26-28).
AS regards claim 19, von Hirschheydt teaches CrossMab antibodies despite having a KIH are not completely free from the LC mispairing
(81) These different approaches for improved heavy chain heterodimerization are contemplated as different alternatives in combination with the heavy-light chain modifications (VH and VL exchange/replacement in one binding arm and the introduction of substitutions of charged amino acids with opposite charges in the CH1/CL interface) in the multispecific antibodies according to the invention which reduce light chain mispairing. However, the preparation of multispecific CrossMAb antibodies optionally in combination with KiH technology is not completely free of mispaired variants thereof.
AS regards claims 20-21 and 24, von Hirschheydt teaches host cell co-expression in CHO cells
(86) In particular, the invention encompasses the separation and/or purification of multispecific CrossMab antibodies, e.g., bispecific CrossMab antibodies, from the products of cells, cell lines and cell cultures. Such products typically include conditioned cell media and/or lysed and homogenized cells and cell cultures (e.g., homogenized cells and cell components within conditioned cell media). The methods of the invention are particularly suited to the processing of products from transgenic host cells, host cell lines and host cell cultures, wherein the transgenic cells, cell lines and cell cultures express the molecule of interest.
(87) The term “host cell” as used in the current application denotes any kind of cellular system which can be engineered to generate the antibodies according to the current invention. In one embodiment HEK293 cells and CHO cells are used as host cells.
AS regards Claim 25, von Hirschheydt teaches compositions for the purified antibody of the method invention
(2) …purity of multispecific CrossMab antibody necessary, e.g. for a pharmaceutical composition comprising said multispecific CrossMab antibody obtained by said methods for use in therapeutic and/or diagnostic applications.
AS regards Claim 27, von Hirschheydt teaches CrossMabs useful as a diagnostic citing such methods of using the antibody
(29) Of particular interest herein are bispecific CrossMab antibodies binding death receptor 5 (DR5) and Human Fibroblast Activation Protein (FAP). A bispecific CrossMab antibody binding DR5 and FAP refers to a bispecific CrossMab antibody that is capable of binding DR5 and FAP with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting cells expressing DR5 and FAP. Specifically, a bispecific CrossMab antibody binding DR5 and FAP refers to a bispecific CrossMab antibody targeting DR5 on a tumor cell and FAP in the stroma surrounding said tumor. The extent of binding of a bispecific antibody that specifically binds death receptor 5 (DR5) and Fibroblast Activation Protein (FAP) to an unrelated, non-FAP or non-DR5 protein may be measured, e.g., by a Enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) based assays (e.g. Biacore) or flow cytometry (FACS).
Whilst von Hirschheydt teaches the elements comprising the instant claim 1, no apparent improved or surprising technical effect is associated with the combination much less in view of the broad scope of claim 1. Instant claim 1 does not proscribe the order in which the method steps are performed, only that a contacting aspect involves multi-mode chromatography material comprising: anion exchange and hydrophobic interactions. von Hirschheydt teaches the art of the chromatography and the art of specific CrossMabs, e.g., Tetravalent, bispecific anti-DR5/anti-FAP bispecific antibodies and tetravalent, bispecific anti-pTau-PS422 antibodies were designed according to the CrossMab and the knob in hole (KiH) technology as described, e.g., in Schaefer et al, PNAS USA 108(2011), 11187-11192, that facilitate the making and using of CrossMabs and the selective elimination of mispaired LCs from the pool of expressed CrossMabs to render the results reasonable and predictable.
9. Claim(s) 3-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over von Hirschheydt et al (US 11945839; 2018-12-20) as applied to claim 1 above, and further in view of Yun et al (J Chromatogr A 2015 Feb 13:1381:173-83. doi:10.1016 /j.chroma. 2014.11.081. Epub 2014 Dec 4).
The method claim 1 relates to a method for the purification of CrossMab VH/VL constructs from light-chain mis-paired variants thereof by mixed mode chromatography using anion exchange and hydrophobic interaction resin in flow-through mode. The claimed method is not limited by the order in which any steps are taken in the generic or dependent claims.
As regards Claims 3-5, Yun teaches a dual functional monolithic cryogel (multi-mode chromatography material) with a combination of functional ligands by anion exchange amine and accessorial hydrophobic benzyl groups, i.e., benzyl-quaternary amine (p. 174, col 1) is suitable for separation of antibodies. Yun teaches the cryogel has anion-exchange function by the electrostatic interaction together with accessorial hydrophobic interaction with protein (BSA), albeit the ion-exchange function is predominated and the hydrophobic function is weak.
The motivation to include specific reactive groups in the multi-mode material to allow the POSA to obtain high purity IgG with the combination of functional ligands of anion-exchange amine and hydrophobic benzyl groups provides the motivation and a predictable and reasonable expectation of success in using such an adsorbent for isolation of bioactive proteins quickly from feedstocks.
10. Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over von Hirschheydt et al (US 11945839; 2018-12-20) as applied to claim 1 above, and further in view of Lee et al ((J Sep Sci. 2017;40:3632–3645).
The method claim 1 relates to a method for the purification of CrossMab VH/VL constructs from light-chain mis-paired variants thereof by mixed mode chromatography using anion exchange and hydrophobic interaction resin in flow-through mode. The claimed method is not limited by the order in which any steps are taken in the generic or dependent claims.
As regards Claim 10, Lee et al (J Sep Sci. 2017;40:3632–3645) teaches the performance of protein separations in mixed-mode chromatography is consequently difficult to predict. In this work, we present a model combining both salt and pH dependence to characterize and to predict protein retention in mixed-mode chromatography. The model parameters are determined based on simple linear pH gradient elution experiments at different ionic strengths and they are directly transferable for the prediction of salt induced elution at fixed pH. Lee uses a CrossMab and its product-related impurities on the multimodal resin CaptoTM MMC in the model system. The presented MMC model is able to describe the retention of the bsAb also at increased ionic strengths. The bsAb used in this work could be bound to the resin at ionic strengths up to 500 mM, which demonstrates the high salt tolerance of the MMC resin. Salt-induced elution was even impossible at pH 5.0. The inclusion of the salt-induced hydrophobic interactions into the model allows the explanation of these observations.
The motivation to include linear pH gradients in the multi-mode material to allow the POSA to refine the purification for different antibody contructs provides the motivation and a predictable and reasonable expectation of success in using such a p-H-based elution for isolation of CrossMabs.
Conclusion
11. No claims are allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643