DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-34, 36-45 have been canceled. Claim 48 has been added. Claims 35, 46, 47, 48 are pending and under consideration.
Applicant's arguments filed 8-12-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This office action is non-final in view of the new anticipation rejections.
Claim objections
Claim 35 is objected to because “a rat and/or human Ig heavy chain constant (Ig CH) gene segments” is grammatically incorrect in number.
The phrase “rat and/or human Ig CH gene segments” in claim 35 need clarified. It appears there may be three types: a rat Ig CH gene, a human Ig CH gene and/or chimeric human/rat Ig CH gene [pg 16, para 114]---.
The phrase “the rat Ig CH gene segments” in claim 46 appears to relate to a chimeric human/rat Ig CH gene [support on pg 16, para 114, description of Fig. 1].
The phrase “the rat Ig CH gene segments” in claim 47 should be changed to ---the rat and/or human Ig CH gene segment--- [support on pg 16, para 114, description of Fig. 1].
Written Description
Claims 46, 47 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Pg 13, para 83, contemplates isolating polyclonal or monoclonal antibodies as newly encompassed by independent claim 48.
The specification lacks written description for an antibody “wherein the Ig CH region of the chimeric immunoglobulin comprises a human CH1 domain and rat CH2, CH3” and optionally rat CH4 domains as required in claims 46 and 47
Fig. 1 is shown below, and pg 16, para 114 (the description of Fig. 1) says the modified rat heavy chain gene has “artificial constant region genes contain[ing] exons encoding a human CH1 domain and rat CH2,3 and 4 domains” (pg 16, para 114).
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Pg 25, para 173, teaches “an exemplary artificial C constant region gene is a constant region gene encoding a human IgG CH1 domain and rat IgG CH2 and CH3 domain.” and pg 27, para 186, teaches: “constant region genes encode a human CH1 domain and rat CH2 CH3 domains, or a human CH1 and rat CH2, CH3 and CH4 domains.” Ig heavy chains have CH1, CH2, and CH3 domains and optionally a CH4 domain:
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However, the specification does not teach the coding sequence of any rat or human CH1, CH2, CH3, or CH4 domains to arrive at the chimeric human/rat CH genes in claim 46 or 47. The specification does not teach any human CH1 coding sequences. The specification does not teach how to replace any rat CH1 coding sequence with any human CH1 coding sequence. The specification does not teach any specific chimeric IgM or IgE CH gene comprising a human CH1 coding sequence, a rat CH2 coding sequence, a rat CH3 coding sequence, and a rat CH4 coding as required in claim 46.The specification does not teach any specific chimeric IgG, IgA, IgD, IgM, or IgE CH gene comprising a human CH1 coding sequence, a rat CH2 coding sequence, and a rat CH3 coding sequence as encompassed by claims 46 and 47.
An adequate written description of a chimeric Ig CH gene requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the nucleic acid sequences used as the basis of the genetic modification, and the human CH1 coding sequence used to make the chimeric Ig CH gene, how to replace the endogenous rat CH1 coding sequence so that it is operably linked to the rat CH2, CH3, and optionally CH4 sequences. It is not sufficient to define chimeric Ig CH gene solely by its principal biological property, i.e. comprising a human CH1 coding sequence and rat CH2, CH3, and optionally CH4 coding sequences, because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any chimeric rat/human Ig CH gene that has the features claimed. Also, naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. Thus, claiming all chimeric Ig CH genes that achieve a result without defining what means will do is not in compliance with the description requirement. Rather, it is an attempt to preempt the future before it has arrived. Accordingly, the concept lacks written description.
In addition, claims 46 and 47 do not require the endogenous rat CH1 coding sequence has been ablated, that the endogenous rat CH1 coding sequence is replaced with a human CH1 coding sequence, that the human CH1 coding sequence is operably linked to the rat CH2, CH3 and optionally CH4 coding sequences, or that the rat expresses a chimeric Ig comprising a constant domain comprising a human CH1 domain, a rat CH2 domain, a rat CH3 domain, and optionally a rat CH4 domain. Therefore, the breadth of chimeric Ig CH domains in claims 46 and 47 lack written description for these reasons.
Enablement
Claims 46, 47 remain 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 chimeric immunoglobulin (Ig) comprising a human Ig VH region operably linked to a rat Ig CH region obtained from a transgenic rat whose genome comprises a replacement of all endogenous Ig VH gene segments replaced with a plurality of human Ig VH gene segments operably linked to a plurality of Ig CH gene segments (Fig. 1), does not reasonably provide enablement for making/using any genetically modified rat as broadly encompassed by claims 46 and 47 to an antibody. 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/or use the invention commensurate in scope with these claims.
The specification does not enable making/using an antibody “wherein the Ig CH region of the chimeric immunoglobulin comprises a human CH1 domain and rat CH2, CH3” and optionally rat CH4 domains as required in claims 46 and 47.
Fig. 1 is shown below, and pg 16, para 114 (the description of Fig. 1) says the modified rat heavy chain gene has “artificial constant region genes contain[ing] exons encoding a human CH1 domain and rat CH2,3 and 4 domains” (pg 16, para 114).
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Pg 25, para 173, teaches “an exemplary artificial C constant region gene is a constant region gene encoding a human IgG CH1 domain and rat IgG CH2 and CH3 domain.” and pg 27, para 186, teaches: “constant region genes encode a human CH1 domain and rat CH2 CH3 domains, or a human CH1 and rat CH2, CH3 and CH4 domains.” Ig heavy chains have CH1, CH2, and CH3 domains and optionally a CH4 domain:
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However, the specification does not teach the coding sequence of any rat or human CH1, CH2, CH3, or CH4 domains to arrive at the chimeric human/rat CH genes in claim 46 or 47. The specification does not teach any human CH1 coding sequences. The specification does not teach how to replace any rat CH1 coding sequence with any human CH1 coding sequence. The specification does not teach any specific chimeric IgM or IgE CH gene comprising a human CH1 coding sequence, a rat CH2 coding sequence, a rat CH3 coding sequence, and a rat CH4 coding as required in claim 46.The specification does not teach any specific chimeric IgG, IgA, IgD, IgM, or IgE CH gene comprising a human CH1 coding sequence, a rat CH2 coding sequence, and a rat CH3 coding sequence as encompassed by claims 46 and 47. The specification does not teach the nucleic acid sequences used as the basis of the genetic modification, the human CH1 coding sequence used to make the chimeric Ig CH gene, or how to replace the endogenous rat CH1 coding sequence so that it is operably linked to the rat CH2, CH3, and optionally CH4 sequences.
In addition, claims 46 and 47 do not require the endogenous rat CH1 coding sequence has been ablated, that the endogenous rat CH1 coding sequence is replaced with a human CH1 coding sequence, that the human CH1 coding sequence is operably linked to the rat CH2, CH3 and optionally CH4 coding sequences, or that the rat expresses a chimeric Ig comprising a constant domain comprising a human CH1 domain, a rat CH2 domain, a rat CH3 domain, and optionally a rat CH4 domain.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use an antibody “wherein the Ig CH region of the chimeric immunoglobulin comprises a human CH1 domain and rat CH2, CH3” and optionally rat CH4 domains as required in claims 46 and 47.
Indefiniteness
Claims 35, 46 and 47 remain 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 pre-AIA the applicant regards as the invention.
Claim 35 is indefinite because “a rat and/or human Ig heavy chain constant (Ig CH) gene segments” is grammatically incorrect in number. Therefore, it is unclear whether claim 35 is limited to “a rat and/or human Ig heavy chain constant (Ig CH) gene segment” or encompasses any number of “rat and/or human Ig heavy chain constant (Ig CH) gene segments”. This is especially confusing in view of claims 46 and 47.
The phrase “the rat Ig CH gene segments encode a human CH1 domain” in claim 46 does not make sense. While a chimeric human/rat Ig CH gene [segment] may encode a human CH1 domain and rat CH2 and CH3 domains, rat gene segments cannot encode a human CH1 domain as claimed.
Claim 47 is indefinite because it does not say whether “the IgCH gene segments” are the rat Ig CH gene segments” refer to the human or rat Ig CH gene segments. It is also unclear because while a chimeric human/rat Ig CH gene [segment] may encode a human CH1 domain and rat CH2 and CH3 domains, rat gene segments cannot encode a human CH1 domain as claimed.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
(e) the invention was described in (1) an application for patent, published under section 122(b), by another filed in the United States before the invention by the applicant for patent or (2) a patent granted on an application for patent by another filed in the United States before the invention by the applicant for patent, except that an international application filed under the treaty defined in section 351(a) shall have the effects for purposes of this subsection of an application filed in the United States only if the international application designated the United States and was published under Article 21(2) of such treaty in the English language.
(e) the invention was described in a patent granted on an application for patent by another filed in the United States before the invention thereof by the applicant for patent, or on an international application by another who has fulfilled the requirements of paragraphs (1), (2), and (4) of section 371(c) of this title before the invention thereof by the applicant for patent.
The changes made to 35 U.S.C. 102(e) by the American Inventors Protection Act of 1999 (AIPA) and the Intellectual Property and High Technology Technical Amendments Act of 2002 do not apply when the reference is a U.S. patent resulting directly or indirectly from an international application filed before November 29, 2000. Therefore, the prior art date of the reference is determined under 35 U.S.C. 102(e) prior to the amendment by the AIPA (pre-AIPA 35 U.S.C. 102(e)).
Claims 35, 46-48 are rejected under pre-AIA 35 U.S.C. 102(b or e) as being anticipated by Hanna (5474755).
Independent claim 48 encompasses any fully human antibody. The process by which it is obtained using a genetically modified rat bears no patentable weight because it does not distinguish the structure/function of a human antibody obtained from a human or a hybridoma in vitro from a human antibody obtained from the genetically modified rat. Hanna taught a human antibody comprising a heavy and light chains comprising human variable domains. The antibody specifically binds a tumor associated antigen. Although the antibody is not made by immunizing a transgenic rat, it has the exact same structure as a human antibody made by the transgenic rat in the “product-by-process” in claim 48. The “process” by which the antibody in claim 48 is made does not distinguish it structurally or functionally from the human antibody described by Hanna.
Dependent claim 35 also encompasses any fully human antibody because, ultimately, the variable, joining, diversity, and constant gene segments can be human. The process by which it is obtained using a genetically modified rat bears no patentable weight because it does not distinguish the structure/function of a human antibody obtained from a human or a hybridoma in vitro from a human antibody obtained from the genetically modified rat. The antibody of Hanna comprising human variable and constant domains is encompassed by claim 35. The structure of the genetic modification in the rat of claim 35 and the “process” by which the antibody in claim 35 is made does not structurally or functionally distinguish the antibody claimed from the human antibody with a human V and C domains described by Hanna.
Claims 46 and 47 have been included because they further limit the rat Ig CH gene segments without excluding human CH gene segments or the production of a fully human antibody. Claim 46 and 47 do not require production of an antibody that contains a human V domain and a C domain comprising a human CH1 domain, a rat CH2 domain, and a rat CH3 domain.
Claims 35 and 48 are rejected under pre-AIA 35 U.S.C. 102(b or e) as being anticipated by McWhirter (9204624).
Independent claim 48 encompasses any fully human antibody. The process by which it is obtained using a genetically modified rat bears no patentable weight because it does not distinguish the structure/function of a human antibody obtained from a human or a hybridoma in vitro from a human antibody obtained from the genetically modified rat. McWhirter taught a transgenic rat whose genome comprises a randomly integrated transgene encoding a rearranged human Ig VH gene segment operably linked to an endogenous Ig CH gene segment (claim 1; description of Fig. 1 and Example 2 (col. 92) and Example 3 (col. 96)). The antibody produced by the rat comprises a human Ig VH region and a rat Ig CH region. The antibody produced by the transgenic rat of McWhirter has the exact same structure as a chimeric human/rat antibody made by the transgenic rat in the “product-by-process” in claim 48. The “process” by which the antibody in claim 48 is made does not distinguish it structurally or functionally from the chimeric human/rat antibody produced by the transgenic rat of McWhirter.
Dependent claim 35 also encompasses any fully human antibody because, ultimately, the variable, joining, diversity, and constant gene segments can be human. The process by which it is obtained using a genetically modified rat bears no patentable weight because it does not distinguish the structure/function of a human antibody obtained from a human or a hybridoma in vitro from a human antibody obtained from the genetically modified rat. The rat of McWhirter produced a chimeric human/rat antibody comprising a human variable domain and a rat constant domain as encompassed by claim 35. The structure of the genetic modification in the rat of claim 35 and the “process” by which the antibody in claim 35 is made does not structurally or functionally distinguish the antibody of claim 35 from the chimeric human/rat antibody with a human V domain and rat C domain produced by the transgenic rat of McWhirter.
Double Patenting
The chimeric antibody claimed is patentably distinct from the rodent germ cell with an endogenous Ig gene inactivated by meganuclease in 8703485 (12130818) and the rat with an ablated endogenous Ig heavy chain gene and/or ablated endogenous Ig light chain gene in 9388233 (13192407).
The rejection of claims 35-39 on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 10072069 (15206063) was withdrawn in view of the terminal disclaimer filed 8-28-23.
Conclusion
Claims 35, 46, 47, and 48 have been allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Green (6833268) taught transgenic mice in which the entire endogenous IgG gene is inactivated and replaced with the entire human IgG gene which contains the Ch1 gene segment (col. 11, lines 24-43; col. 12, line 51; col. 14, line 29; col. 25, line 53).
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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