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 .
Claims Status
Claims 1, 3-5, 14-19, 26-28, 60, 100-101, 104, 107, and 110 are pending and are examined on the merits.
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.
Claims 26-28 and 60 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.
Each of Claims 26-28 recite a list of alternative limitations, however the list lacks a conjunction (“and” or “or”) between the elements, and it is therefore unclear whether all of the recited substitutions/sequences are required or if the claim is drawn to each one individually. For the purposes of examination, the claims are construed to be drawn to any one (or more) of the recited options, rather than all in combination. This rejection can be overcome by adding an “or” between the final two elements in each list.
For example, Claim 28 could read:
The composition of claim 27, wherein the antibody heavy chain A (HC-A) and antibody heavy chain B (HC-B) comprises at least one HC-HC assembly promoter pair comprising the following amino acid sequence located in the CH3 domain:
-HC-HC-PP3: SEQ ID NO: 104 on HC-A; SEQ ID NO: 105 on HC-B
-HC-HC-PP4: SEQ ID NO: 106 on HC-A; SEQ ID NO: 107 on HC-B
-HC-HC-PP5: SEQ ID NO: 108 on HC-A; SEQ ID NO: 109 on HC-B; or
-HC-HC-PP18: SEQ ID NO: 112 on HC-A; SEQ ID NO: 113 on HC-B.
In addition, Claims 26-27 recite “(numbering according to EU numbering of the CH3 domain)” in parentheses. It is therefore unclear if this recitation is merely exemplary of a numbering scheme, or if the claims require said numbering scheme. This rejection can be overcome, for example, by removing the parentheses: e.g. “...comprising the following amino acid substitutions
Claim 60 is drawn to a composition of up to four nucleic acid sequence sets “selected from” options (i)-(iv). When a Markush claim is structured such that a limitation is “selected from” a group of alternatives, this grouping needs to be closed (See MPEP 2117). In the instant case, use of the conjunction “and/or” make it unclear which members belong to the Markush group. This rejection can be overcome by replacing the “and/or” with an “and”.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-5, 14-19, 26-28, 60, 100-101, 104, 107, and 110 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a composition for expression of at least two antibodies and associated methods wherein the nucleic acid sequence sets encode whole IgG antibodies, does not reasonably provide enablement for the same compositions or methods wherein the nucleic acid sequence sets encode a “fragment thereof” or any of the additional antigen binding molecules encompassed by the term “antibody” as defined in the instant specification. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and, (8) the breadth of the claims. In re Wands, 8 USPQ2d, 1400 (CAFC 1988).
The term “antibody” is defined by the instant specification very broadly as “any type of antigen binding molecule” or a “polypeptide that specifically recognizes and/or binds to a particular target” (Pg. 3, lines 33-41). While the term is inclusive of “whole antibodies” as conventionally understood (Pg. 3, line 39), it further encompasses countless other molecules, including many that share little to no structural similarity with conventional immunoglobulins such as “synthetic antibodies” and “antibody mimetics” (Pg. 4, line 18).
The specification further states a “fragment” of an antibody is “preferably understood” as comprising “at least one functional CDR of the corresponding antibody capable of recognizing (and binding to) an antigen or target”. However, additional examples of molecules encompassed by the term “antibody fragment” include those lacking the antigen-binding domain entirely (e.g. Fc, pFc’) (Pg. 5, line 3). Accordingly, an antibody “fragment” is interpreted in its broadest sense to encompass any polypeptide comprising any portion of any of the polypeptides encompassed by the term “antibody” as understood above.
In addition, the term “antibody chain assembly promoter” is defined as “at least one moiety (e.g. an amino acid) that promotes, supports, forces, or directs the correct assembly of at least two antibody polypeptide chains” and “suppresses or reduces mis-assembly” (Pg. 23, lines 11-18).
Accordingly, the “composition for expression of at least two antibodies” of instant Claim 1 minimally requires nucleic acid sequences encoding any “fragment” of any two antibody heavy chains and but a single amino acid in either fragment which promotes the “correct assembly” of the two HC fragments.
The examples provided by the instant specification describe compositions encoding pairs of IgG1 antibodies wherein one IgG1 is unmodified and the second comprises paired “HC-HC assembly promoters” (Example 2; Table 5) or wherein both IgG1 antibodies comprise different HC-HC assembly promoters (Example 3; Table 6). This same scheme is further shown to allow for expression of three different antibodies comprising three different sets of HC-HC assembly promoters (Example 6; Table 8). Further, Example 7 demonstrates that administration of lipid nanoparticles comprising the nucleic acid sets results in the desired expression of the correctly assembled antibody mixtures in vivo (Pg. 120-121).
It is well known in the art that expression of conventional IgG antibodies first requires proper folding and assembly of the complete quaternary structure comprising two heavy chains and two light chains. For example, Feige et al 2009 (Molecular cell, 34(5), 569-579.; PTO-892) teaches that unassembled IgG heavy chains are actively retained in the endoplasmic reticulum, and that the intrinsically disordered CH1 domain folds only upon interaction with the light chain CL domain (Abstract). Consistent with the teachings of the prior art, each of the examples described comprises nucleic acid sets encoding whole IgG1 antibodies comprising complete heavy and light chain polypeptides.
However, there are no examples or guidance provided by the instant specification of compositions “for expression of at least two antibodies” – or methods of producing antibodies from said compositions – comprising any of the additional molecules encompassed by the term “antibody” as defined by the specification, neither are there any examples of the invention comprising only a “fragment” of said molecules. Moreover, as described a “method of treating” a condition appears to require a functional antigen binding domain (Pg. 103-109), however the compositions as claimed are drawn more broadly to antibody “fragments” with no clear medical use.
As such, one of ordinary skill in the art would be faced with an undue amount of experimentation in order to make and/or perform the invention commensurate in scope with the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-5, 14-19, 26, 100, 104, 107, and 110 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yan et al. 2017 (WO 2017/205014 A1; PTO-892), herein “Yan”.
Regarding instant Claims 1, 3-5, 14-19, and 100, Yan teaches compositions (e.g. vectors, host cells, nucleic acids, etc.) for expressing a mixture of at least two antibodies from a single cell wherein heavy chain (HC) Fc domains of at least one of the antibodies comprises partner-directing mutations (i.e. an “antibody chain assembly promoter”) favoring specific HC-HC pairing and disfavoring heterodimerization with an unmodified Fc domain (Pg. 36-37; Abstract; Fig. 1).
Yan further teaches that examples of an “alteration that disfavors heterodimers” include substitutions of charged residues or steric protuberances/knobs, and that such substitutions can be made at “domain interface residues” or contacting residues within the human IgG CH3-CH3 interface (Pg. 37-38, § “alteration that disfavors heterodimers”; Table 4).
Regarding instant Claim 26, Yan teaches at least one antibody in the mixture comprises a pair of mutations, wherein the mutations comprise K409E on the first heavy chain and D399K on the second heavy chain (Fig. 12).
Regarding instant Claims 104 and 107, Yan teaches that nucleic acids encoding the mixture of antibodies can be carried on a viral vector or encased in liposomes, which in turn can be administered to a patient or directly to a tumor in the patient in order to treat a disease (pg. 66, lines 3-11; Pg. 68, lines 1-13). Regarding instant Claim 107, administering a viral vector or liposome containing the nucleic acids encoding for the mixture of antibodies would inherently result in “expressing” the antibodies “in an organ or tissue” in the subject.
Regarding instant Claim 110, Yan teaches mixtures of antibodies can be produced by a host cell in vitro via a method comprising “introducing DNA encoding the mixtures of antibodies described herein into host cells, culturing the host cells, and recovering the mixture of antibodies from the cell mass or culture medium” (Pg. 50, § “Mixtures of Antibodies and Methods of Producing Them”).
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.
Claims 101 is rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. 2017 (WO 2017/205014 A1; PTO-892), herein “Yan”, as applied to claim 1 above.
The teachings of Yan are summarized above.
Yan does not teach a “kit” comprising the composition for expression of at least two antibodies.
However, Yan further teaches that the compositions can be formulated as a liquid, gel, paste, etc. comprising additional buffering components (Pg. 52 ¶3) and contemplates several different routes of administering nucleic acids encoding the mixture of antibodies such as injection, inhalation, or topical administration (Pg. 66, ¶2).
It would have been obvious to one of ordinary skill in the art that the composition for expressing two or more antibodies and pharmaceutical formulations thereof could be supplied as a “kit” comprising the necessary components to administer the composition, such as a container with the pharmaceutical formulation of the composition and a syringe, inhaler, etc. The skilled artisan would be motivated to put together such a “kit” for the convenience of having all the necessary components available prior to administering the composition as taught by Yan. Moreover, regarding the limitation that the kit further comprises “technical instructions”, MPEP 2112.01(III) states that printed matter that is not functionally related to the product does not distinguish the claimed product from the prior art.
Claims 27-28 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. 2017 (WO 2017/205014 A1; PTO-892), herein “Yan”, as applied to claims 1, 4-5, 14, and 26 above, and further in view of Von Kreudenstein et al. 2013 (Mabs. Vol. 5. No. 5. Taylor & Francis, 2013.), herein “Von Kreudenstein”, and as evidenced by PDB entry 4BSW (https://www.rcsb.org/fasta/entry/4BSW/display).
The teachings of Yan are summarized above.
Yan does not teach the particular substitutions within the claimed assembly promoter pairs “PP3”, “PP4”, “PP5”, or “PP18”. This deficiency is cured by Von Kreudenstein.
Von Kreudenstein teaches heterodimeric Fc domain “ZW1” comprising paired substitutions T350V/L351Y/F405A/Y407V on heavy chain A and T350V/T366L/K392L/T394W on heavy chain B, which drive specific HC-HC pairing with a purity greater than 95% (Fig. 1B). Von Kreudenstein teaches that unlike prior heterodimeric mutations, like a conventional knob-into-hole (KiH), the ZW1 Fc variant has comparable thermal stability to the wild type Fc domain (Fig. 2A).
Von Kreudenstein further teaches that the structure and sequence of the “ZW1” variant was deposited in PDB as entry “4BSW” (Pg. 647, last ¶). The sequence reported in 4BSW comprises identical sequences to SEQ ID NOs: 108 and 109 (https://www.rcsb.org/fasta/entry/4BSW/display; see alignment below).
SEQ108 1 EPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
4BSW_1 124 EPQVYVYPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 183
SEQ108 61 ALVSKL 66
||||||
4BSW_1 184 ALVSKL 189
SEQ109 1 EPQVYVLPPSRDELTKNQVSLLCLVKGFYPSDIAVEWESNGQPENNYLTWPPVLDSDGSF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
4BSW_2 124 EPQVYVLPPSRDELTKNQVSLLCLVKGFYPSDIAVEWESNGQPENNYLTWPPVLDSDGSF 183
SEQ109 61 FLYSKL 66
||||||
4BSW_2 184 FLYSKL 189
It would have been obvious to one of ordinary skill in the art to substitute the paired K409E and D399K fc mutations taught by Yan with the paired T350V/L351Y/F405A/Y407V and T350V/T366L/K392L/T394W Fc mutations of Von Kreudenstein to arrive at a composition for expressing a mixture of antibodies wherein one of said antibodies comprises a HC-HC assembly promoter pair identical to instantly claimed “PP5”. The skilled artisan would have been motivated to employ the Fc mutations taught by Von Kreudenstein owing to their high pairing specificity and improved thermal stability. There would have been a reasonable expectation of success because Yan teaches that the residues mutated in Von Kreudenstein are Fc-Fc domain interface residues and that additional alterations within these contacting residues including steric protuberances could be employed in the context of the disclosed invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
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/BRYAN WILLIAM HECK/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643