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 .
Claim Status
Applicant’s amendments and remarks, filed 03/07/2025, are acknowledged.
Claims 4, 6-9, 12-18, 20-24, 26-33, 35-48, 50-59, and 62 are canceled.
Claims 1, 25, 60, 65, 72, and 74-77 are amended.
Claims 1-3, 5, 10-11, 19, 25, 34, 49, 60-61, and 63-77 are pending.
As such, claims 1-3, 5, 10-11, 19, 25, 34, 49, 60-61, and 63-77 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Withdrawn Objections
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 03/07/2025.
Withdrawn Rejections
Applicant’s arguments, see pages 11-13, filed 03/07/2025, with respect to claims 1-3, 5, 10-11, 19, 25, 34, 49, 60-61, and 63-77 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive in part. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Specifically, Examiner acknowledges that claim 1 was amended to remove the language “vice versa” and “are each independently of each other”, the “first part” or “second part” of the non-antibody multimeric polypeptides comprise one or two ectodomains of 4-1BBL or OX40L, and Examiner acknowledges that the fusion polypeptides require specific domains but the source is not necessary; claims 25 and 72 were amended to remove the language “an amino acid sequence”; and, claims 64-66 were amended to have sufficient antecedent basis. As such, the rejection under 35 USC 112(b) is withdrawn in part.
Applicant’s arguments, see pages 13-18, filed 03/07/2025, with respect to claims 1-3, 5, 10-11, 34, 49, 60-61, and 63-77 rejected under 35 USC 112(a) as allegedly lacking written description have been fully considered and are persuasive. The issue regarding the specification failing to disclose the structure-function correlation of the claimed antibody-multimer-fusion polypeptide have been sufficiently addressed through amendments to the claims and Applicant’s arguments. Particularly, Examiner agrees with Applicant’s argument that the present invention is drawn to a method of making, thus every component of the product does not need to be described. As such, the rejection under 35 USC 112(a) is withdrawn.
New Objections
Claim Objections
Claims 25 and 60 are objected to because of the following informalities:
Claim 25: “the second fusion polypeptide comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 56, SEQ ID NO: 3 or SEQ ID NO: 4” should read “the second fusion polypeptide comprises the amino acid sequence
Claim 60: The description of the third recombination recognition sequence is broken up into several bullet points instead of being one continuous line (i.e., “a third recombination recognition sequence located between the first and the second recombination recognition sequence, and between the third and the fourth expression cassette”).
Claim 60: remove “and” after “a fourth expression cassette encoding the antibody heavy chain”.
Appropriate correction is required.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(b)
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 1-3, 5, 10-11, 19, 25, 34, 49, 60-61, and 63-77 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.
Claim 1 recites “the non-antibody multimeric polypeptide two ectodomains” and “the non-antibody multimeric polypeptide only one ectodomain”. These phrases are incomplete because it is unclear which transitional phrase Applicant would use to describe these non-antibody multimeric polypeptides. As such, the scope of the claims (claim 1 and the dependent claims) is indefinite.
Maintained Rejections
Claim Rejections - 35 USC § 112(b)
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 1-3, 5, 10-11, 19, 25, 34, 49, 60-61, and 63-77 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.
Claim 1 recites the limitation "the second part of the non-antibody multimeric polypeptide" in subpart (b). There is insufficient antecedent basis for this limitation in the claim.
Claims 1, 19, 34, and 69-72 recite “a binding site that specifically binds to an antigen”. It is unclear if the phrase describes a required characteristic of the binding site, or if the phrase is referencing a binding site and a method step.
The phrase “partly 5’ and partly 3’” in claims 64-66 is a relative term which renders the claim indefinite. The phrase “partly 5’ and partly 3’” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification nor the claims define what sequences/positions are encompassed by the term “partly”. As such, one would not be apprised as to where the selection marker is located.
Applicant’s Arguments
Applicant respectfully traverses the rejections as follows:
The Office Action further states at page 5 that there is insufficient antecedent basis for the phrase "the second part of the non-antibody multimeric polypeptide" in claim 1, subpart (b). This has been amended herein to "a second part of the non-antibody multimeric polypeptide". As such, claim 1 is sufficiently definite under 35 U.S.C. § 112(b) on this basis.
The Office Action further states on page 6 that claims 1, 19, 34 and 69-72 are indefinite in the recitation of "a binding site specifically binding to an antigen" because it is allegedly not clear whether this is a characteristic of the binding site or if the phrase is referencing a method step. Claim 1 has been amended to specify instead a binding site "that specifically binds to an antigen", obviating this basis of rejection. As such, claims 1, 19, 34 and 69-72 are sufficiently definite under 35 U.S.C. § 112(b) on this basis.
The Office Action further states on page 6 that claims 64-66 are indefinite in the recitation of "partly 5' and partly 3"'. Respectfully, the meaning of this phrase in claim 64 is evident from claims 65 and 66, and a person of skill in the art would accordingly readily understand the boundaries of these claims. As such, claims 64-66 are sufficiently definite under 35 U.S.C. § 112(b) on this basis.
Response to Arguments
Applicant's arguments filed 03/07/2025 have been fully considered but they are not persuasive.
Applicant indicates that the phrase “the second part of the non-antibody multimeric polypeptide" in claim 1, subpart (b) has been amended; however, the claim still recites the phrase.
Applicant indicates that the phrase “a binding site specifically binding to an antigen” in claims 1, 19, 34, and 69-72 have been amended; however, claim 1 was the only claim that was amended. Further, the amendment does not overcome the rejection because it remains unclear if the phrase described a required characteristic of the binding site, or if the phrase is referencing a binding site and a method step. It is recommended that Applicant amend the claims to recite “specifically binds is capable of specifically binding to an antigen” to overcome the rejection.
Examiner respectfully disagrees with Applicant’s assertion that the meaning of the phrases “partly 5’” and “partly 3’” are evident from claims 65 and 66, and a person of skill in the art would accordingly readily understand the boundaries of these claims. Claim 64 recites that the expression cassette encoding for a selection marker is located either: i) 5’, or ii) 3’, or iii) partly 5’ and partly 3’ to the third recombination recognition sequence. With the recitation of 5’ or 3’ in relation to the third recombination recognition sequence, it remains unclear what is distinguishing between those terms and the “partly 5’ and partly 3’” phrase. Under the broadest reasonable interpretation, one would understand that 5’ or 3’ to the third recombination recognition sequence would encompass any space to the left or right of the third recombination recognition sequence, respectively. Lastly, Claims 65 and 66 simply describe what the expression cassette comprise of, and does not provide any definition for what is meant by the term “partly”.
As such, the 112(b) rejections are maintained.
Claim Rejections - 35 USC § 112(a)-Written Description
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 19 and 25 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a method for producing an antibody-multimer-fusion polypeptide comprising an antibody heavy chain, an antibody light chain, a first fusion polypeptide and a second fusion polypeptide, comprising: transfecting a mammalian cell with expression cassettes for the antibody heavy chain, the antibody light chain, the first fusion polypeptide and the second fusion polypeptide at a stoichiometric ratio of 1:1:2:1; and culturing said mammalian cell under conditions in which the antibody heavy chain, the antibody light chain, the first fusion polypeptide and the second fusion polypeptide are expressed; and thereby producing the antibody-multimer-fusion polypeptide, wherein the antibody-multimer-fusion polypeptide comprises (a) said antibody heavy chain and said antibody light chain, and (b) said first fusion polypeptide comprising in N- to C-terminal direction a first part of a non-antibody multimeric polypeptide, an antibody heavy chain CH1 domain or an antibody light chain constant domain, an antibody hinge region, an antibody heavy chain CH2 domain and an antibody heavy chain CH3 domain, and said second fusion polypeptide comprising in N- to C-terminal direction the second part of the non- antibody multimeric polypeptide and an antibody light chain constant domain if the first fusion polypeptide comprises an antibody heavy chain CH1 domain or an antibody heavy chain CH1 domain if the first fusion polypeptide comprises an antibody light chain constant domain, wherein (i) the antibody heavy chain of (a) and the first fusion polypeptide of (b) are covalently linked to each other by at least one disulfide bond, (ii) the antibody heavy chain of (a) and the antibody light chain of (a) are covalently linked to each other by at least one disulfide bond, and (iii) the first fusion polypeptide of (b) and the second fusion polypeptide of (b) are covalently linked to each other by at least one disulfide bond, and wherein the variable domains of the antibody heavy chain and the antibody light chain form a binding site that specifically binds to an antigen, wherein (i) the first fusion polypeptide comprises as said first part of the non-antibody multimeric polypeptide two ectodomains of a Tumor Necrosis Factor (TNF) ligand family member that are connected to each other by a peptide linker, and the second fusion polypeptide comprises as said second part of the non-antibody multimeric polypeptide only one ectodomain of said TNF ligand family member, or (ii) the first fusion polypeptide comprises as the first part of the non-antibody multimeric polypeptide only one ectodomain of said TNF ligand family member, and the second fusion polypeptide comprises as the second part of the non-antibody multimeric polypeptide two ectodomains of a TNF ligand family member that are connected to each other by a peptide linker; and wherein the TNF ligand family member is 4-1BBL or OX40L.
Claim 19 is drawn to the method according to claim 1, wherein the variable domains of the antibody heavy chain and the antibody light chain form a binding site specifically binding to a cell surface antigen selected from the group consisting of Fibroblast Activation Protein (FAP), Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), Epidermal Growth Factor Receptor (EGFR), Carcinoembryonic Antigen (CEA), CD19, CD20 and CD33.
Claim 25 is drawn to the method according to claim 1, wherein (a) the antibody heavy chain and the antibody light chain form a binding site capable of specific binding to a target cell antigen, and (b) the first fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 57, SEQ ID NO: 58 or SEQ ID NO: 59, and the second fusion polypeptide comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 56, SEQ ID NO: 3 or SEQ ID NO: 4.
The specification disclose of a heteromultimeric antibody-multimer-fusion comprising a pair of an antibody heavy chain and an antibody light chain forming a binding site for human FAP and a first fusion polypeptide and a second fusion polypeptide wherein in the multimer is trimeric human 4-1BBL (see pg. 40, lines 11-15). In a first set of experiments, transient production of an anti-FAP antibody-4-1BBL multimer-fusion was performed (see pg. 40, lines 19-20). A set of vectors, each comprising only a single expression cassette for a single polypeptide of the antibody-multimer-fusion, was used at different defined stoichiometric ratios (see table on page 20). It can be seen that an expression cassette ratio of 1:1:2:1 resulted in the best results and an overall 20% higher effective titer as well as a 35% higher than the 1:1:2:2 expression cassette ratio (see pg. 41, lines 1-3). In a second set of experiments, transient production of the anti-FAP antibody-4-1BBL multimer-fusion was performed (see pg. 41, lines 5-6). A set of vectors, comprising one or two expression cassettes each for a single polypeptide of the antibody-multimer-fusion, was used at different defined stoichiometric ratios (see pg. 41, lines 6-8; see 1st table on page 42). It can be seen that an expression cassette ratio of 1:1:2:1 results in the best results and an overall 40% higher effective titer as well as a 67% higher effective titer than the 1:1:2:2 expression cassette ratio (see pg. 42, lines 5-7). In a third set of experiments stable production of the anti-FAP antibody- 4-1BBL multimer-fusion (see pg. 42, lines 9-10). A set of vectors, comprising one or two expression cassettes each for a single polypeptide of the antibody-multimer-fusion, was used at different defined stoichiometric ratios (see pg. 42, lines 10-12; see 2nd table on pg. 42). Sixty plates with single cell clones were cultivated for each of the ratios of experiment 1 and experiment 2 (see pg. 42, lines 20-23; see 1st and 2nd tables on pg. 43). It can be seen that for the 1:1:2:1 expression cassette ratio (1:1+1 vector ratio) a better growth (recovery), a double number of wells with more than 20% confluence as well as a double number of titer positive clones compared to the 1:1:2:2 expression cassette ratio (1:2 vector ratio) is obtained (see pg. 43, lines 2-5). Lastly, in regard to anti-FAP antibody-4-1BBL multimer-fusion, the specification discloses of an experiment wherein the multimer-fusion was performed using targeted integration (see pg. 45, lines 1-3). The targeted integration was performed using a double recombinase mediated cassette exchange reaction with Cre-recombinase (see pg. 45, lines 4-6). It can be seen that an expression cassette ratio of 1:1:2:1 resulted in the best results and an overall 45% higher effective titer as well as a 45% higher effective titer than the 1:1:2:2 expression cassette ratio (see pg. 45, lines 16-18; see tables on pg. 45).
The specification also disclose of a set of experiments wherein transient production of an anti-CEA antibody-4-1BBL multimer-fusion was performed (see pg. 44, lines 11-12). It can be seen that an expression cassette ratio of 1:1:2:1 results in the best result and an overall 15% higher effective titer as well as a 24% higher effective titer than the 1:1:2:2 expression cassette ratio (see pg. 44, lines 19-21; see table on pg. 44).
The specification disclose of a set of experiments transient production of an anti-CD19 antibody-4-1BBL multimer-fusion was performed (see pg. 45, lines 20-21). A set of vectors, each comprising only a single expression cassette for a single polypeptide of the antibody-multimer-fusion, was used at different defined stoichiometric ratios (see table on pg. 46). It can be seen that an expression cassette ratio of 1:1:2:1 results in the best results and an overall 9% higher effective titer as well as a 23% higher effective titer than the 1:1:2:2 expression cassette ratio (see pg. 46, lines 6-8).
However, the specification fails to disclose that Applicant was in possession of claimed method of producing an antibody-multimer-fusion. Particularly, the specification fails to disclose of the structure of the antibody-multimer-fusion proteins. Specifically, the specification fails to disclose that Applicant was in possession of the claimed method wherein the variable domains of the antibody heavy chain and the antibody light chains bind to any antigen, excluding FAP, CD19, and CEA. Additionally, the specification fails to disclose Applicant was in possession of the claimed method wherein the non-multimeric polypeptide comprised of ectodomains of OX40L. Lastly, the specification fails to disclose that Applicant was in possession of the claimed method wherein the antibody-multimer-fusion components are driven by a SV40 promoter.
Although the specification discloses anti-FAP antibody-4-1BBL multimer-fusion, anti-CEA antibody-4-1BBL multimer-fusion, and anti-CD19 antibody-4-1BBL multimer-fusion, the specification does not disclose the sequences of these multimer-fusion proteins; additionally, the claims are not limited to any particular construct, and are inclusive of any antigen and any fusion polypeptides comprising ectodomains of 4-1BBL or OX40L. This indicates that there are hundreds, if not thousands, of possible antibody-multimer-fusions encompassed by the claims. Thus, the claims encompass a vast genus of methods of producing antibody-multimer-fusions that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of antibody-multimer-fusions because, inter alia, the specification does not disclose a correlation between the necessary structure of the antibody-multimer-fusions and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Further, the specification fails to provide method steps that result in producing antibody-multimer-fusions. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecules function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of methods of producing antibody-multimer-fusions and variants thereof claimed only by a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibody-multimer-fusions has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of methods of producing an antibody-multimer-fusion polypeptide. The disclosure of only one or two 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.") (MPEP 2163).
The instant claims do not fully describe the structure of the first and second fusion polypeptides to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of antibody-multimer-fusions, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous antibody-multimer-fusions had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of antibody-multimer-fusions claimed only by a partial structure and functional characteristic(s). Thus the antibody-multimer-fusions described by the instant claims encompasses an overly broad genus, the structure of the first and second fusion polypeptides, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of antibody-multimer-fusions by the functions of the antibody heavy chain, antibody, light chain, first fusion polypeptide, and second fusion polypeptide. Additionally, the claims attempt to define the genus of antibody-multimer-fusions by reciting sequences in claims 25, 34, 69-72, and 76-77. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claims.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) 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.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed antibody-multimer-fusions, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the challenges of manufacturing fusion proteins, Challener (BioPharm International 30 (5) 2017: 30-31, 37; previously submitted with the Office Action mailed 09/30/2024) disclose that achieving and maintaining proper folding for each of the components in fusion proteins is a major challenge in the molecular design of these products (see pg. 31, middle column). As a result, combining the different components of the fusion protein that do not naturally occur together can lead to instability with the composite molecule, creating manufacturing challenges such as aggregation during the cell culture or purification steps (see pg. 31, middle column). Some fusion proteins are also prone to proteolytic degradation during production and/or after therapeutic administration (see pg. 31, middle column). In addition to stability issues, Challener disclose that other manufacturing challenges include low expression titers, and incomplete and heterogeneous glycosylation (see pg. 31, right column). The titers for fusion proteins are generally lower than those for mAbs due to less efficient translation (see pg. 37, right column).
Additionally, Johari et al (Biotechnol. Bioeng. 2015;112: 2527–2542; previously submitted with the Office Action mailed 09/30/2024) disclose that while cell lines such as Chinese hamster ovary (CHO) cells remain the predominant host for the commercial production of recombinant therapeutic proteins (see pg. 2527, right column); however, as effective as CHO cells are as cell factories for many recombinant products, productivity is unpredictably low (see pg. 2528, left column). Even mAb protein products in the same isotype/sub-class can display variable expression levels due to different translational and post-translational process rates; this can also be expected with artificial fusion proteins which have not co-evolved as two (or more) combined components and may, therefore, have differing domain-specific folding and/or secretion requirements (see pg. 2528, left column).
As such, the art describes the low productivity of fusion proteins in CHO cells and low titers due to less efficient translation can make producing these fusion proteins unpredictable and inefficient.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA, an adequate written description 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 (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of methods of producing antibody-multimer-fusion polypeptide.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed bispecific antibodies or immunoconjugates. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of recombinant proteins as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
Applicant traverses the written description rejection as follows:
The Office Action states that the claims lack written description because "the specification fails to disclose that Applicant was in possession of [the] claimed method [because it] fails to disclose of [sic] the structure of the first and second fusion polypeptides. In particular, the Office Action at page 18 states that "the instant case has many similarities to AbbVie" [Abbvie v. Centocor (Fed. Cir. 2014).] Abbvie involved claims to antibodies that met certain binding characteristics per se, and to a method of treating rheumatoid arthritis using such antibodies. The asserted claims in Abbvie, however, were not directed to methods of making multimer antibodies. Similarly, the Office Action at page 19 cites University of Rochester v. G. D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004) for the proposition that an inventor must "provide a description of the compound sufficient to distinguish infringing compounds from noninfringing compounds, or infringing methods from non-infringing methods." This only applies, however, to claims to (1) the compounds themselves, or to (2) methods of using those compounds. In stating that the present case is similar to Abbvie or Rochester, the Office Action misapprehends the nature of the invention… The invention is a method of making such fusion proteins in which the method depends not at all on which targets the fusion proteins bind. Instead, the claimed method depends only upon how the highly-conserved components of such molecules interact with each other. As such, the number of potential species encompassed by the claimed method is relatively low, and Applicant has provided a representative number of such species… the Office Action again misunderstands the nature of the presently-claimed invention; here, the recited antibody-multimer-fusion polypeptides are not "described in terms of a method of [their] making", rather, the claims recite a method of making the polypeptides. The recited fusion proteins are not being claimed; the method of making them is. There is no function to couple in the context of the present claims…
The Office Action contends that "the specification does not disclose the sequences of [the disclosed FAP, CEA and CD19] multimer fusion proteins; additionally, the claims are not limited to any particular construct, and are inclusive of any antigen and any fusion polypeptides comprising ectodomains of 4-1BBL or OX40L. This indicates that there are hundreds, if not thousands, of possible antibody-multimer-fusions encompassed by the claims." This statement is not accurate… Applicant therefore provides the sequences necessary for performance of the method. (Because the CDR sequences do not materially affect assembly of the antibody-multimer-fusion polypeptides, they need not be described with particularity.)… The Office Action further argues at page 22 that "[u]pholding claims drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies," citing Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc) (citing, in turn, Fiers v. Revel, 984 F.2d at 1171). The present claims are not drawn to a genus of antibodies. Similarly, the Office Action at page 22 argues that "Possession [of a genus of fusion proteins] may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features." Applicant is not attempting to show possession of a genus of fusion proteins. The case law the Office Action cites is misapplied to the presently-claimed method.
The Office Action at page 20 cites Challener, "Fusion Proteins Pose Manufacturability Challenges", BioProcess Int'l 30(5):30-31, 37 (2017) in an effort to show that the alleged challenges to manufacturing fusion proteins make their production inefficient and unpredictable (and therefore, presumably insufficiently described). However, Challener at page 31 states about a particular TNFR-Fc fusion protein that "the Fc provides stability. In fact, the most successful fusion proteins to date have been so-called Fc fusion proteins." The antibody Fc region, of course, comprises the CH2 and CH3 domains recited in the present claims. As such, Challener supports the adequacy of the written description of the present claims. The Office Action at page 21 further cites Johari, "Integrated Cell and Process Engineering for Improved Transient Production of a "Difficult-to-Express" Fusion Protein by CHO Cells", Biotechnol. Bioengineering 112L2527-2542 (2015) in an effort to demonstrate that expression of the fusion proteins in Chinese Hamster Ovary (CHO) cells is too unpredictable to support written description. This argument is not credible, however, because, as Johari itself acknowledges, CHO cells are the industry standard for protein expression, and whatever variability using them entails is well-understood by persons of skill in the art.
Response to Arguments
Applicant's arguments filed 03/07/2025 have been fully considered but they are not persuasive.
Examiner acknowledges that the claims are drawn to a method of producing antibody-multimer-fusion polypeptides and not necessarily the composition itself. As such, issues regarding the specific organization of the fusion polypeptides of the antibody-multimer-fusion polypeptides are withdrawn. However, claims 19 and 25 require specific binding activity (e.g., specifically binding to a cell surface antigen) for the antibody heavy and light chains but there is insufficient description of the structure of these domains that will result in the claimed function. The teachings of Abbvie and Rochester, while drawn to insufficient written description of a composition or methods of using the composition, are relevant to the present case because these cases supported that an adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed as stated in MPEP 2163. As stated in the rejection above, the specification fails to disclose that Applicant was in possession of a method of producing antibody-multimer-fusion polypeptides wherein the first fusion and second fusion polypeptides comprise of OX40L ectodomains or wherein the expression of the antibody and fusion polypeptides are driven by SV40 promoter. Additionally, dependent claims 19 and 25 require specific functions for the antibody heavy chain and light chain. While some of the arguments above are drawn to the structure of the antibody-multimer-fusion polypeptides, the same argument can be made for the method of producing which is there is insufficient structure-function correlation between what is claimed and what the specification discloses, and Applicant was not in possession of the claimed invention at the time of filing; thus, one of skill in the art cannot easily envisage the claimed invention. The specification fails to demonstrate that producing antibody-multimer-fusion polypeptides with OX40L ectodomains and SV40 promoter will result similarly to the antibody-multimer-fusion polypeptides comprising 4-1BBL ectodomains disclosed in the specification. The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). The claims are not limited to the antibody-multimer-fusion polypeptides described in the arguments, and instead encompass a large genus of admixtures (e.g., mammalian cells and OX40L ectodomains) wherein the antibody heavy chain and antibody light chain require specific functions, for which Applicant has not demonstrated possession of at the time of filing nor are adequately described for one of skill in the art to envisage the structure-function correlation. While one can substitute the 4-1BBL ectodomains with OX40L ectodomains, the fact that any experimentation is required to figure out exactly what is encompassed necessarily means that Applicant has not sufficiently described the claimed subject matter. It should also be mentioned that the enablement of the invention has not been rejected by the Examiner.
Furthermore, the teachings of Challener and Johari further demonstrate the unpredictability of producing proteins based on the various factors that go into this process (e.g., mammalian cell); thus, without sufficient written description one of skill would not be apprised of how the claimed invention will function. Challener disclose that achieving and maintaining proper folding for each of the components in fusion proteins is a major challenge in the molecular design of these products (see pg. 31, middle column). As a result, combining the different components of the fusion protein that do not naturally occur together can lead to instability with the composite molecule, creating manufacturing challenges such as aggregation during the cell culture or purification steps (see pg. 31, middle column). Some fusion proteins are also prone to proteolytic degradation during production and/or after therapeutic administration (see pg. 31, middle column). In addition to stability issues, Challener disclose that other manufacturing challenges include low expression titers, and incomplete and heterogeneous glycosylation (see pg. 31, right column). The titers for fusion proteins are generally lower than those for mAbs due to less efficient translation (see pg. 37, right column). Examiner acknowledges that pg. 31 of Challener disclose of a particular TNFR-Fc fusion protein that the Fc provides increased stability; however, Challener discloses the name of the fusion protein (i.e., etanercept), thus one of skill would know the structure of the Fc region and subsequently the other domains of the protein.
Additionally, in respect to Applicant’s arguments regarding the teachings of Johari, Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the argument is not credible without specifically pointing out how the language of the claims patentably distinguishes them from the references. While Johari et al disclose that while cell lines such as Chinese hamster ovary (CHO) cells remain the predominant host for the commercial production of recombinant therapeutic proteins (see pg. 2527, right column), it is also noted, however, as effective as CHO cells are as cell factories for many recombinant products, productivity is unpredictably low (see pg. 2528, left column). Even mAb protein products in the same isotype/sub-class can display variable expression levels due to different translational and post-translational process rates; this can also be expected with artificial fusion proteins which have not co-evolved as two (or more) combined components and may, therefore, have differing domain-specific folding and/or secretion requirements (see pg. 2528, left column). Thus, the art describes the low productivity of fusion proteins in CHO cells and low titers due to less efficient translation can make producing these fusion proteins unpredictable and inefficient.
As such, the written description rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
17/811,376
Claims 1-3, 5, 10-11, 25, 49, 60-61, 63-68, 73, and 75-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-20 of copending Application No. 17/811,376 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘376 application is drawn to a 4-1BBL trimer-containing antigen binding molecule comprising (a) an antigen binding domain capable of specific binding to PD-L1,(b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen binding molecule is characterized in that the first polypeptide comprises two ectodomains of 4-1BBL or a fragment thereof that are connected to each other by a peptide linker and in that the second polypeptide comprises one ectodomain of 4-1BBL or a fragment thereof, and (c) an Fc domain composed of a first and a second subunit capable of stable association (see claim 1). The ‘376 application is drawn to the isolated nucleic acid molecule encoding the 4-1BBL trimer-containing antigen binding molecule of claim 1 (see claim 16). The ‘376 application is drawn to a vector, particularly an expression vector, comprising the isolated nucleic acid molecule of claim 16 (see claim 17). The ‘376 application is drawn to a host cell comprising the nucleic acid of claim 16 (see claim 18). The ‘376 application is drawn to a method of producing the 4-1BBL trimer-containing antigen binding molecule, comprising culturing the host cell of claim 18 under conditions suitable for expression of the 4-1BBL trimer-containing antigen binding molecule (see claim 19). The ‘376 application is drawn to the method of claim 19, further comprising recovering the antibody from the host cell (see claim 20).
The difference between the instant application and the ‘376 application is that the instant application is drawn to a method of producing the product and the ‘376 application is drawn to nucleic acids, vector, and host cell. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed method of producing of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. In the instant case, the ‘376 application discloses that the method of producing the TNF trimer-containing antigen binding molecule provides expression vector comprising the isolated polynucleotide of the invention and a host cell comprising the isolated polynucleotide or the vector of the invention wherein the host cell is a mammalian cell (see claim 19 and Example 1). While the ‘376 application discloses that the cells were transfected with the expression vectors at a 1:1:1:1 ratio (see pg. 77, lines 2-5), Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization – Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability
of subject matter encompassed by the prior art unless there is evidence indicating such
concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed
in the prior art, it is not inventive to discover the optimum or workable ranges by routine
experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed
process which was performed at a temperature between 40°C and 80°C and an acid
concentration between 25% and 70% was held to be prima facie obvious over a reference
process which differed from the claims only in that the reference process was performed at a
temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330,
65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already
generally known provides the motivation to determine where in a disclosed set of percentage
ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ
809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the
references were held to be unpatentable thereover because, among other reasons, there was
no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.).
For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d
804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147,
14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir.
1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree
“will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle
of law that a mere carrying forward of an original patented conception involving only change of
form, proportions, or degree, or the substitution of equivalents doing the same thing as the
original invention, by substantially the same means, is not such an invention as will sustain a
patent, even though the changes of the kind may produce better results than prior inventions.”).
See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution
in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration
schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration
schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or
efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to
improve upon what is already generally known,” it would have been prima facie obvious to one of
ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment
period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective
Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular
parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a
recognized result, before the determination of the optimum or workable ranges of said variable
might be characterized as routine experimentation, because “obvious to try” is not a valid
rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite
number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals
to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the
combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market
pressure to solve a problem and there are a finite number of identified, predictable solutions, a
person of ordinary skill has good reason to pursue the known options within his or her technical
grasp. If this leads to the anticipated success, it is likely the product not of innovation but of
ordinary skill and common sense. In that instance the fact that a combination was obvious to try
might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-
effective variable would be one, but not the only, motivation for a personal of ordinary skill in
the art to experiment to reach another workable product or process.
In the instant case, instant claim 1 is drawn to a stoichiometric ratio of 1:1:2:1 which achieves a recognized result, such as an effective titer. Accordingly the recited stoichiometric ratio is a result - effective variable that achieve a recognized result, such as an effective titer for protein production, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the stoichiometric ratio recited is prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments
Applicant traverses the provisional nonstatutory double patenting rejection.
As an initial matter, Applicant notes that the Office Action at page 26 cites the Manual of patent Examining Procedure 2144.05(II(A) and states that: “Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the "normal desire of scientists or artisans to improve upon what is already generally known," it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention”. Applicant respectfully points out that the present claims are directed to methods of producing an antibody-multimer-fusion polypeptides, and not drug dosages, administration schedules, or treatment periods. As such, the above analysis is not germane to the pending claims.
The Office Action relies entirely on the concept of a "result-effective variable" to establish obviousness. To establish obviousness, the Office Action must establish that a particular variable (i.e., claim limitation) would affect the desired outcome; that is, that the variable is result-effective. "The idea behind the 'result-effective variable' analysis is... that a person of ordinary skill would not always be motivated to optimize a parameter 'if there is no evidence in the record that the prior art recognized that particular parameter affected the result." (Genentech, Inc. v. Hospira, Inc. 946 F.3d 1333, 1341 (Fed. Cir. 2020)). Moreover, "[t]he absence of any disclosure regarding the relationship between the variable and the affected property may preclude a finding that the variable is result-effective." (In re Applied Materials, Inc., 692 F.3d 1289, 1297 (Fed. Cir. 2012)).
Here, the Office Action relies on the assumption that the ratio between heavy chain, light chain, first polypeptide and second polypeptide recited in the claims is a result-effective variable. To this end, the Office Action points to the single disclosure in the reference application that the ratio between these four polypeptides is 1:1:1:1. However, this disclosure, alone, fails to establish the ratios between the four polypeptides - and in particular, the ratio between the first polypeptide and second polypeptide - is result-effective; that is, that adjusting the ratios would improve production of the resulting antibody-multimer fusion polypeptide. (The disclosure of the present application cannot be used to establish this.) The Office Action points to nothing else that would establish the particular ratio between the four polypeptides as result-effective. As such, the Office Action does not make out a prima facie case of obviousness. Cf. In re Yates, 663 F.3d 1054 (C.C.P.A. 1981) (Claims not obvious because prior art reference did not establish that the parameter in question was result- effective).
Response to Arguments
Applicant's arguments filed 03/07/2025 have been fully considered but they are not persuasive.
Examiner acknowledges that the present claims are directed to methods of producing an antibody-multimer-fusion polypeptides, and not drug dosages, administration schedules, or treatment periods. However, the listing of drug dosages, administration schedules, and treatment periods are merely examples of variables that can be optimized (or manipulated) through routine experimentation. Similarly to these variables, the claimed stoichiometric ratio of expression cassettes is another variable that can be optimized through routine experimentation to improve production. While the specification of the ‘376 application disclose that the ratio between the four polypeptides is 1:1:1:1, Applicant is reminded that this is a double patenting rejection thus the language of the claims is being examined. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). As stated above, the ‘376 claims are drawn to a 4-1BBL trimer-containing antigen binding molecule comprising (a) an antigen binding domain capable of specific binding to PD-L1,(b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen binding molecule is characterized in that the first polypeptide comprises two ectodomains of 4-1BBL or a fragment thereof that are connected to each other by a peptide linker and in that the second polypeptide comprises one ectodomain of 4-1BBL or a fragment thereof, and (c) an Fc domain composed of a first and a second subunit capable of stable association (see claim 1); an isolated nucleic acid molecule encoding the 4-1BBL trimer-containing antigen binding molecule of claim 1 (see claim 16); a vector, particularly an expression vector, comprising the isolated nucleic acid molecule of claim 16 (see claim 17); a host cell comprising the nucleic acid of claim 16 (see claim 18); a method of producing the 4-1BBL trimer-containing antigen binding molecule, comprising culturing the host cell of claim 18 under conditions suitable for expression of the 4-1BBL trimer-containing antigen binding molecule (see claim 19); and, the method of claim 19, further comprising recovering the antibody from the host cell (see claim 20).
Under the broadest reasonable interpretation, the limitations of the ‘376 claims fall within the scope of the present claims because the claimed invention of the ‘376 application is claiming a method of producing a 4-1BBL trimer-containing antigen binding molecule comprising (a) an antigen binding domain capable of specific binding to PD-L1,(b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen binding molecule is characterized in that the first polypeptide comprises two ectodomains of 4-1BBL or a fragment thereof that are connected to each other by a peptide linker and in that the second polypeptide comprises one ectodomain of 4-1BBL or a fragment thereof, and (c) an Fc domain composed of a first and a second subunit capable of stable association (see claim 1). Therefore, the 1:1:2:1 ratio of the present claims are encompassed within the method of producing as recited in claim 19 of the ‘376 application.
As such, the provisional double patenting rejection is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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