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 .
Specification
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
The instant application contains polynucleotide and/or polypeptide sequences. Applicant is required to review the specification for compliance with the above.
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.
Claims 1, 2, 5-13, 17 and 24 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 rejected claims cover antigen-binding molecules, antibodies and antigen-binding fragments thereof and conjugates that specifically binds to IgM µ-chain.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”).
With regard to the recited genus of antigen-binding molecules, antibodies and antigen-binding fragments thereof that specifically binds to IgM µ-chain, the following applies:
Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed. Cir. 2010) states that “...a generic claim may define the boundaries of a vast genus of chemical compounds...the question may still remain whether the specification, including the original claim language, demonstrates that the applicant invented species sufficient to support a claim to a genus”. See page 1171.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
See also Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a “laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species.
Amgen, Inc. v. Chugai Pharmaceutical Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) states that “it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it”.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or structural features common to the members of the genus, which features constitute a substantial portion of the genus, so that one of skill in the art can “visualize or recognize” the members of the genus (Emphasis added). Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
Courts have stated that “[i]n claims involving [non-genetic] chemical materials, generic formulae usually indicate with specificity what the generic claims encompass. One skilled in the art can distinguish such a formula from others and can identify many of the species that the claims encompass. Accordingly, such a formula is normally an adequate description of the claimed genus.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). (emphasis added).
There is no such specificity here, nor could one skilled in the art identify molecules and antibodies encompassed by the rejected claims. Specifically, Applicant fails to disclose any other antibodies, besides those covered by the SEQ ID’s in the specification and claims, and in relation to the above, these disclosed species or subgenre do not represent the substantial variety covered by the genus of antigen-binding molecules, antibodies and antigen-binding fragments thereof that specifically binds to IgM µ-chain.
With regard to the functional definition of specifically binds to IgM µ-chain, the specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116) because the specification contains almost no information by which a person of ordinary skill in the art would understand that the inventors possessed the all of the recited molecules and antibodies. At best, it simply indicates that one should test an infinite number of molecular entities to see if these moieties can perform the required binding. In this connection, the specification contains no generic structural or characteristics of those compounds which bind an IgM µ-chain besides those antibodies instantly disclosed, see In re ’318 Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009) (“[A]t the end of the day, the specification, even read in light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient.”).
The Examiner acknowledges that a working example or exemplified embodiment is not necessarily a requirement for description. However, where a generic claim term is present in a claim, as in the present application, and defined only by functional characteristics, the specification must convey enough information, e.g., via sufficient representative examples, to indicate invention of species sufficient to constitute the genus. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 967 2 (Fed. Cir. 2002). The written description requirement “requires a description of an invention, not an indication of a result that one might achieve if one made that invention.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997); see also Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1350 (Fed. Cir. 2013) (“A patent...‘is not a reward for the search, but compensation for its successful conclusion.’ ... For that reason, the written description requirement prohibits a patentee from ‘leaving it to the ... industry to complete an unfinished invention.’” (citations omitted)).
Accordingly, the specification lacks adequate written description for the recited antigen-binding molecules, antibodies and antigen-binding fragments thereof and conjugates that specifically binds to an IgM µ-chain.
Claims 1-4, 9-13, 17 and 24 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 rejected claims cover antigen-binding molecules that bind to an IgM µ-chain that are not antibodies or antigen-binding fragments thereof.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”).
With regard to the recited binding moieties, the following applies:
Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed. Cir. 2010) states that “...a generic claim may define the boundaries of a vast genus of chemical compounds...the question may still remain whether the specification, including the original claim language, demonstrates that the applicant invented species sufficient to support a claim to a genus”. See page 1171.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
See also Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a “laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species.
Amgen, Inc. v. Chugai Pharmaceutical Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) states that “it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it”.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or structural features common to the members of the genus, which features constitute a substantial portion of the genus, so that one of skill in the art can “visualize or recognize” the members of the genus (Emphasis added). Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
Here, Applicant desires patent protection for binding moieties for an IgM µ-chain However, other than antibodies and their functional fragments, the specification does not provide adequate written description of the claimed genus of these targeting moieties. This is because antibodies are well characterized, functionally and structurally, in the prior art. Specifically, antibodies are heavy (~150 kDa) globular plasma proteins. The size of an antibody molecule is about 10 nm. They have sugar chains (glycans) added to conserved amino acid residues. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds. Each chain is composed of structural domains called immunoglobulin domains. These domains contain about 70–110 amino acids and are classified into different categories (for example, variable or IgV, and constant or IgC) according to their size and function. They have a characteristic immunoglobulin fold in which two beta sheets create a "sandwich" shape, held together by interactions between conserved cysteines and other charged amino acids.
Some parts of an antibody have the same functions. The arms of the Y, for example, contain the sites that can bind to antigens (in general, identical) and, therefore, recognize specific foreign objects. This region of the antibody is called the Fab (fragment, antigen-binding) region. It is composed of one constant and one variable domain from each heavy and light chain of the antibody. The paratope is shaped at the amino terminal end of the antibody monomer by the variable domains from the heavy and light chains. The variable domain is also referred to as the FV region and is the most important region for binding to antigens. To be specific, variable loops of β-strands, three each on the light (VL) and heavy (VH) chains are responsible for binding to the antigen. These loops are referred to as the complementarity determining regions (CDRs). 1 There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, on the amino acid sequence of a variable domain of an antigen receptor. Since the antigen receptors are typically composed of two variable domains (on two different polypeptide chains, heavy and light chain), there are six CDRs for each antigen receptor that can collectively come into contact with the antigen. A single antibody molecule has two antigen receptors and therefore contains twelve CDRs total. There are three CDR loops per variable domain in antibodies.2
However, in contrast to the function of antibodies and their functional fragments, as outlined above, the other targeting moieties covered by the claims are not sufficiently characterized by the specification or state of the art in such a manner that those of ordinary skill would understand that the instant inventors knew how to they would be structurally integrated to bind to an IgM µ-chain. In particular, the specification does not provide any examples of the other targeting moieties besides antibodies, and in this way, the specification does not present the requisite examples of ligands and targeting moieties, given the breadth and variety of these groups covered by the claims. Specifically, the specification does not disclose a sufficient description of a representative number of species, either by actual reduction to practice, or by disclosure of relevant, identifying generic characteristics, i.e., structure or other physical and/or chemical properties, of those moieties which can be used to bind an IgM µ-chain.
Moreover, the specification contains almost no information by which a person of ordinary skill in the art would understand that the inventors possessed these moieties, which have the structural characteristics, as outlined above, which can properly function as claimed. In this connection, the specification contains no generic structural or specific functional characteristics of the recited binding moieties.
Accordingly, the specification lacks adequate written description for the recited binding molecules that are not antibodies or antigen-binding fragments thereof.
Claims 1, 2, 5-13, 17-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejected claims cover antigen-binding molecules, antibodies and antigen-binding fragments thereof and conjugates that specifically binds to IgM µ-chain.
Here, a genus of antigen-binding molecules, antibodies and antigen-binding fragments thereof and conjugates that specifically binds to IgM µ-chain, lack written description because the recited functional definition of the molecules and antibodies does not describe the claimed invention.
Here, the genus of molecules and antibodies cannot be adequately described by functional characteristics of preferential binding, even where there is disclosed or known correlations between structure and function.
The Examiner recognizes that the target, an IgM µ-chain, my be fully characterized. Previously, disclosing a bonding target, such as an IgM µ-chain, satisfied the written description requirement for a claim to an antibody or protein that binds the target. The Federal Circuit's decisions in Enzo Biochem v. Gen-Probe, Inc., 323 F.3d 956, 964 (Fed. Cir. 2002) and Noelle v. Lederman, 355 F. 3d 1341 (Fed. Cir. 2004) which purportedly set forth what has been called the "newly characterized antigen" test. Also, the PTO's Written Description Training Materials Revision dated March 25, 2008, provide an example (Example 13) embodying the test set forth in Enzo and Noelle.
However, reliance on Enzo and Noelle is misplaced. While the court in Noelle did discuss what is referred to as the "newly characterized antigen" test, the Federal Circuit has recently rejected such a test. Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378-79 (Fed. Cir. 2017). At issue in Amgen was the district court's jury instruction which read:
In the case of a claim to antibodies, the correlation between structure and function may also be satisfied by the disclosure of a newly characterized antigen by its structure, formula, chemical name, or physical properties if you find that the level of skill and knowledge in the art of antibodies at the time of filing was such that the production of antibodies against such an antigen was conventional and routine.
Id. at 1376. The Federal Circuit concluded that the instruction was "not legally sound and [was] not based on any binding precedent." Id. In reaching its conclusion the Federal Circuit reviewed the cases which purported to set forth the newly characterized antigen test including Noelle. Id. at 1376-77. The court concluded that in each of the prior cases the reference to the newly characterized antigen test was dicta and not binding precedent. Id.
The Federal Circuit went on to find that the newly characterized antigen test ran afoul of the Federal Circuit's precedent in Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane). Id. at 1378. The court noted that the focus of the inquiry is whether the written description contains enough information about the claimed products. Id. The court held that describing the antigens, which was not the claimed invention, did not satisfy the written description requirement when (“it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid... does not tell you anything at all about the structure of the antibody [emphasis applied]"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In a memo issued in February 2018, USPTO, Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, Feb. 22, 2018 (available at https://www.usnto.gov/sites/defauH/files/documents/amgen 22feb2018.pdf) the PTO issued a clarification regarding the law of written description as it applies to antibodies stating:
In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
The Memo goes on to state that
"Examples in the 2008 Written Description Training Materials Are Outdated." and should NOT be relied upon as reflecting the current state of the law. Id. at 2. The Memo explains that
USPTO personnel should continue to follow the guidance in the MPEP regarding written description (see, e.g., MPEP 2161.01 and 2163 ), except insofar as MPEP 2163 indicates that disclosure of a fully characterized antigen may provide written descriptive support of an antibody to that antigen.
Id.
The instant claims present the same deficiency as the claims in Amgen where there is no evidence that knowledge of the chemical structure of an IgM µ-chain gives the required kind of structure-identifying information about the corresponding peptides that it binds. As in Amgen, the instant claims attempt to describe ofCS-binding VAR2CSA polypeptides by describing the target to which the peptides bind. Moreover, there is nothing else in the disclosure that describes the peptides as required by the test set forth in Ariad.
Moreover, as outlined above, the functional definition of an IgM µ-chain-binding molecule or antibody does not clearly allow persons of ordinary skill in the art to recognize that he or she invented these molecules (see Vas-Cath at page 1116) because the specification contains almost no information by which a person of ordinary skill in the art would understand that the inventors possessed the of the recited molecules or antibodies.
Accordingly, the specification lacks adequate written description for the recited antigen-binding molecules, antibodies and antigen-binding fragments thereof and conjugates that specifically binds to IgM µ-chain.
Claim 4 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(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.
Claim 4 covers VH and VL regions comprising amino acid sequences having at least 70% sequence identity to recited seqiences.
How much homology is required to claim a variant of a known nucleic acid sequence when the function of the nucleic acid is recited in the claims was directly answered by Ex parte Livshits (Appeal 2013-001807; US Patent Application 11/106,455):
https://www.bradley.com/insights/publications/2016/02/how-much-homology-is-enough-under--112
The answer in this case was no. The PTAB agreed with the Examiner that a PHOSITA could envision sequences that met the percent identity requirement and hybridized under the recited conditions to SEQ ID NO:3.
Further, the Examiner admitted that by using conservative substitutions, a PHOSITA could likely envision a DNA sequence that encoded a polypeptide having the same tertiary structure as the polypeptide encoded by SEQ ID NO:3.
However, the PTAB found there was no teaching that the conservation of structure (whether in the DNA or encoded polypeptide) would be a surrogate for conservation of the function claimed (over-expression of L-amino acids in the culture medium).
In other words, PTAB wanted some teaching as to which of the 5 pent of residues of the in the recited single domain antibody could be altered while still conserving the function of the encoded polypeptide.
The specification demonstrated the recited function for the polypeptide encoded by SEQ ID NO:3, but offered no teaching as to what regions of the recited protein were critical for conservation of the recited function and which regions could be modified.
The PTAB stated that the specification “leaves it to others to discover the nature and scope of substitutions, deletions, and insertions that can be made to arrive at a 95% homology sequence that additionally allows for recited activity.”
The applicants attempted to use BLAST homology data to argue that a PHOSITA would be able to address the issue, but the evidence was accorded little weight and characterized as an “invitation to experiment” by the PTAB.
The PTAB also noted that even though the DNA/polypeptides that could be envisioned by the PHOSTIA could be easily tested as set forth in the specification for conservation of the recited function, this was not enough to describe the structure so that a PHOSITA could determine “beforehand whether or not a particular structure meets the functional requirements.” As such, the PTAB held that for a nucleic acid variant which is claimed by homology and function of the expressed protein, the PHOSITA must be able to determine if the nucleic acids claimed produce a protein that accomplished the recited function from the specification itself in order to meet the written description requirement.
Therefore, in the instant case, a PHOSITA must be able to determine if a peptide that satisfies the percent identity can perform the required IgM binding from the specification itself in order to meet the written description requirement.
However, the specification here leaves it to others to discover the nature and scope of substitutions, deletions, and insertions that can be made to arrive at a 70% identity that additionally allows for the required activity since the specification offered no teaching as to what regions of the recited molecules were critical for conservation of the recited function and which regions could be modified, see In re ’318 Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009) (“[A]t the end of the day, the specification, even read in light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient.”).
Even though the DNA/polypeptides that could be envisioned by the PHOSTIA could be easily tested as set forth in the specification for conservation of the recited function, this is not enough to describe the structure so that a PHOSITA could determine beforehand whether or not a particular structure meets the functional requirements.
Accordingly, a PHOSITA cannot determine if a peptide that satisfies the recited percent identity can also perform the required IgM binding from the specification itself in order to meet the written description requirement
Claim 24 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention.
“The standard for determining whether the specification meets the enablement requirement [in accordance with the statute] was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). See also United States v. Telectronics, Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988) ("The test of enablement is whether one reasonably skilled in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation."). A patent need not teach, and preferably omits, what is well known in the art. In re Buchner, 929 F.2d 660, 661, 18 USPQ2d 1331, 1332 (Fed. Cir. 1991); Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384, 231 USPQ 81, 94 (Fed. Cir. 1986), cert. denied, 480 U.S. 947 (1987); and Lindemann Maschinenfabrik GMBH v. American Hoist & Derrick Co., 730 F.2d 1452, 1463, 221 USPQ 481, 489 (Fed. Cir. 1984). Determining enablement is a question of law based on underlying factual findings. In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991); Atlas Powder Co. v. E.I. du Pont de Nemours & Co., 750 F.2d 1569, 1576, 224 USPQ 409, 413 (Fed. Cir. 1984).” See M.P.E.P. § 2164.
Here, the nature of the invention is an antibody, antigen-binding fragments thereof and chimeric molecules comprising the same that bind to an antigen on the CLBL-1 cancer cell line, and methods of treating cancer with these antibodies and chimeric molecules.
In this regard, determining how a particular antibody will impact the body is not routine and the level of ordinary skill in the art of treating cancer is high, as an ordinary artisan in this art needs specialized knowledge of the complex nature of cancer and immunology. Applicant is reminded of the heightened enablement for these types of inventions: Specifically, the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. [I]n the field of chemistry generally, there may be times when the well-known unpredictability of chemical reactions will alone be enough to create a reasonable doubt as to the accuracy of a particular broad statement put forward as enabling support for a claim. This will especially be the case where the statement is, on its face, contrary to generally accepted scientific principles. Most often, additional factors, such as the teachings in pertinent references, will be available to substantiate any doubts that the asserted scope of objective enablement is in fact commensurate with the scope of protection sought and to support any demands based thereon for proof. [Footnote omitted.].
However, the claims are drawn to an antigen-binding molecule that specifically binds to IgM µ-chain antigen. The claims also cover methods of treating a disease or condition associated with an undesired expression of IgM µ-chain antigen in a subject.
Therefore, either the state of the art or the specification needs to establish that an antibody or chimeric molecules comprising the same that bind to an antigen on the CLBL-1 cancer cell line can also bind IgM µ-chain antigen and treat a disease or condition associated with an undesired expression of IgM µ-chain antigen in a subject.
The prior art teaches that CLBL-1 is an in vivo model that provides a highly stable tool for B-cell lymphoma research in veterinary and human medicine, see Rütgen et al., PLoS One. 2012;7(6) (“In the present study we could show that the canine cell line CLBL-1 is capable of inducing tumor (lymphoma) formation in mice. These tumors are morphologically and phenotypically similar to the canine end-stage disease. This fact makes the model an interesting candidate for further investigations into the diagnosis and therapy of canine lymphoma and has the potential to promote the translational and comparative lymphoma research in humans and dogs.”)
Therefore, the use of the instant antibodies against CLBL-1 can be characterized as “known”, but use of such antibodies to target other antigens, such as IgM µ-chain, is not predictable. For instance, there is no nexus between the preferred binding of an antibody against one target and its activity against a second target. Thus, it is unpredictable whether antibody used for canine cancer treatment targeting CLBL-1 can also be used to target canine IgM µ-chain, since there doesn’t appear to be a link between antibody binding between the two targets.
The specification fails to remedy the state of the art. Here the specification only shows activity of the binding of the instant antibodies to an antigen present on the CLBL-1 cell line. Therefore, a nexus may be established between these results with binding an antigen on CLBL-1 and the treatment of cancer. The specification does not provide any additional examples or guidance on how to use the recited antibodies to bind canine IgM µ-chain. Thus, the specification provides sufficient teachings only for the enablement of binding CLBL-1. The prior art provides no compensatory guidance and it would require undue experimentation to practice the invention for binding the canine IgM µ-chain. The amount of experimentation would be undue because it would require determining how to use the antibodies to bind the canine IgM µ-chain and how cancer can be treated by such activity. Specifically, as outlined above, it is not routine to determine how an antibody will act on complex biochemistry to treat different cancer. In the instant case, it is only known that the instant anti-CLBLK-1 antibodies, and its conjugates, have cytotoxic activity against CLBL-1 cancer cells. This means that significant experimentation would be required to determine how the antibodies can be used to bind IgM µ-chain and how this binding can treat cancer. Those of ordinary skill in the art cannot extrapolate between the anti-CLBL-1 activity of the antibodies and any binding to the IgM µ-chain. Moreover, there is little guidance, in both the prior art and the specification, with respect to the use of such antibodies to treat cancer.
Claim Rejections - 35 USC §§ 101, 112(a)
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 24 is rejected under 35 U.S.C. 101 because the claimed invention is not supported by the utility asserted in the claims.
The claims are drawn to an antigen-binding molecule that specifically binds to IgM µ-chain antigen. The claims also cover methods of treating a disease or condition associated with an undesired expression of IgM µ-chain antigen in a subject.
However, the disclosure only covers an antibody, antigen-binding fragments thereof and chimeric molecules comprising the same that bind to an antigen on the CLBL-1 cancer cell line, and methods of treating cancer with these antibodies and chimeric molecules.
Claim 24 is also rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph (statutory basis, listed above). Specifically, because the claimed invention is not supported by the utility asserted in the claims or a well-established utility for the reasons set forth above, one skilled in the art clearly would not know how to use the claimed invention.
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.
Claim 1-13, 17 and 24 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.
The structural criteria of life-extending moiety in claim 10 is not defined.
The claims recite antigen-binding molecules that bind to IgM µ-chain antigen, but the specification indicates that the recited sequences (claim 3 and 4) are for antibodies that bind to antigens on CLBL-1 cancer cell line. Therefore, the intended target of the antigen-binding molecules is unclear.
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, 2, 5-8 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lacave, Géraldine & Cox, Eric & Goddeeris, Bruno. (1997). CROSS-REACTION OF ANTISERA AGAINST IMMUNOGLOBULINS OF SEVERAL SPECIES WITH DOLPHIN IMMUNOGLOBULINS (Lacave).
Regarding antigen-binding molecule in claims 1, 2, 5-8 and 17, Lacave teaches goat anti-dog IgM (mu chain), see page 89.
Claims 9 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lawrence et al., Veterinary Immunology and Immunopathology 65 (1998) 89-96 (Lawrence).
Regarding the chimeric molecules covered in the rejected claims, Lawrence teaches goat anti-dog IgM-mu chain conjugated with horseradish peroxidase (HRP), see page 91.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at telephone number 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
1 See https://en.wikipedia.org/wiki/Antibody
2 See https://en.wikipedia.org/wiki/Complementarity-determining_region