DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/17/26 has been entered. Claims 1,12, 23-24, 29-31 and 36-37 have been amended. Claim 17 remains withdrawn as being directed to a non-elected invention. Accordingly, claims 1, 7-10, 12-13 and 23-37 are under examination.
Withdrawn Rejections
All rejections of claims not reiterated herein, have been withdrawn.
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, 7-10, 12-13 and 23-37 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.
Regarding the pending claim language of claims 1, 24 and 31, the recited language limits the claims to an antibody, however said antibody (is described only in terms of function rather than structure. In particular, the claims may be interpreted as reciting that the antibody, that has certain desired binding properties, namely that it binds to and forms a complex with pro-neurotensin 1-117 (SEQ ID NO: 5),
Regarding claims 1, 24 and 31, the claims encompass a large genus of products that may be characterized by substantial variability; put another way, the claimed genus encompasses many possible species of antibodies such monoclonal antibodies, polyclonal antibodies and antibody fragments each potentially binding one or multiple different fragments as claimed, each characterized by a potentially different antibody sequences. For example, regarding the hybridoma obtained antibodies, every hybridoma created is going to produce a specific antibody, no two having the same sequence.
The claims encompass a large and highly variable genus as there is no way to visualize what antibodies (which specific antibodies characterized by their own distinct sequences of heavy and light chain regions) would bind the specific fragments as claimed (the binders are described only in terms of what they bind, i.e. the antigens to which they bind, rather than structure specific to the binders themselves), and the claims are not limited to any particular antibody producing hybridoma cell line(s). The recited claim language attempts to place limitations on the specific binders by what they do, and as a result places no limitations on the sequences/structure of the binders themselves (rather defines the binders only in terms of desired binding properties, thereby limiting the binders of the claimed methods only to those that achieve the desired functions).
The claim scope is potentially enormous depending on how many potential species of the recited genus that meet the structural requirements also meet the functional requirements (the binding described). The originally filed specification fails to disclose any sufficient identifying characteristics specific to the claimed genus of antibodies such to correlate antibody structure with the recited function in a way that would allow one to readily visualize what species of the claimed genus would also exhibit the required functional ability. For example, even in the case of binders that are antibodies, one cannot readily visualize the structure(s) of the antibodies that would be encompassed by the recited claims. Without some identified structure, one cannot readily distinguish between those binders encompassed by the recited language, from those excluded from the claim. As an example, consider binders that are antibodies: one cannot readily visualize what anti-enkephalin antibodies exhibit the desired binding functions, and bind one of the claimed fragments from those known anti-pro-neurotesin antibodies that do not bind these fragments. As presented (referring to claims 1, 24 and 31), the pending claim language would encompass any and all antibodies produced by any hybridoma cell line produced using B-cells from a mammal immunized with pro-enkephalin. Having the sequences of the fragments as claimed (i.e., fragments to which the binder binds) fails to provide sufficient structure specific to the antibodies (binders) to allow one to distinguish what species achieve the desired binding functions from those that do not.
The originally filed specification fails to identify any particular species reading on the claimed genus.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding, binding to a certain epitope), “[c]laiming
antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2
specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. vy. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Along these same lines, a more recent Federal Circuit decision, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself; not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date” (AbbVie, 759 F.3d at 1298, reiterating Enzo Biochem, Inc., 323 F.3d at 964)(emphasis added).
In the present case, there is insufficient evidence of such an established structure-function correlation in the case of antibodies, for example, that bind the very specific fragments identified by the claimed SEQ ID Nos.
A claimed invention 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. A biomolecule defined solely by its ability to perform a function, such as to serve as an antigen recognizing construct, without a known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest, see MPEP 2163.
As discussed in the recent case of Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), see page 17: An adequate written description must contain enough information about the actual makeup of the claimed products—“a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” which may be present in “functional” terminology “when the art has established a correlation between structure and function.” Ariad, 598 F.3d at
1350. But both in this case and in our previous cases, 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 on PCSK9 .. . does not tell you anything at all about the structure of the antibody”); 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).
Amgen Inc. v. Sanofi further notes, pointing to Ariad Pharms., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed Cir. 2010): To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date.” Id. at 1350. Demonstrating possession “requires a precise definition” of the invention. Id. To provide this “precise definition” for a claim to a genus, a patentee must disclose “a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can visualize or recognize’ the members of the genus.” Id. Amgen at pages 7-8.
In this case, there is no disclosure of any species such to be sufficient to represent the claimed genus of binders having the recited functional properties. There is substantial variability in the genus. Since there are a substantial variety of compounds possible within the genus, without disclosure of any common partial structure or
other sufficient identifying characteristics of the genus, the claimed genus is not sufficiently described.
Regarding predictability, without some guidance such as structure-function correlation, it is not possible to visualize the species encompassed by the genus based on recitation of function alone. The teachings of Harlow & Lane (Antibodies, A Laboratory Manual, Cold Spring Harbor laboratory, 1988, pages 25-26 and 37-59) describe how the steps of the humoral immune response to an immunogen are dependent on APC, T-cell and B-cell recognition and processing of the immunogen in ways well known in the art to be highly unpredictable and heavily influenced by the particular immunogen and the specifics of the immunization protocol. Harlow
et al. teach that even small changes in structure, such as loss of a single hydrogen bond, can profoundly affect antibody-antigen interaction (p. 25, last paragraph to page 26, second paragraph).
The principles laid out in Harlow are further illustrated in the teachings of Edwards et al.("The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS"” J. Mol. Biol. (2003) 334, 103-118, DOI:10.1016/).jmb.2003.09.054), which shows the immense combinatorial flexibility and capacity of the human antibody repertoire to generate binding sites to an individual protein antigen, the B-lymphocyte growth factor known as “BLyS” (see entire document). Edwards describes in detail how the breadth of antibody structures against a given immunogen can be influenced by the immunization and/or selection methods (see Discussion Section).
Lloyd et al. ("Modelling the human immune response: performance of a
10e11 human antibody repertoire against a broad panel of therapeutically relevant antigens”, Protein Engineering, Design and Selection, Volume 22, Issue 3, 1 March 2009, Pages 159-168, https://doi.org/10.1093/protein/gzn058) also shows a repertoire of 1x1011 human antibody variable regions can generate large numbers of unique, biologically active scFvs against a variety of polypeptide targets (see e.g., at page 161-62 bridging paragraph and in Table 1, cited herewith).
Further, as another example in the art illustrating the potential scope of the genus of binders (e.g., just with respect to antibodies) encompassed by the pending claim language, see also Meyer et al., (“New Insights in Type I and II CD20 Antibody Mechanisms-Of-Action With a Panel of Novel CD20 Antibodies”, British Journal of Haematology, 2018, 180, 808-820, |https://doi.org/10.1111/bjh.15132). Meyer describes the core binding region of the well-known anti-CD20 antibody rituximab corresponds to amino acid residues 170ANPS173, wherein N171 is the key residue for binding. By contrast, the OBZ and B1 anti-CD20 antibodies share an overlapping epitope with rituximab (170OANPSEKNSP178); however, in contrast to rituximab residues at positions 176-178 contribute the most to binding (see page 809, left col., 2nd full paragraph). Meyer also described the production and characterization of a panel of new anti-CD20 antibodies which were shown to bind epitopes contained within or nearby the rituximab 170ANPS173 epitope but to bind to different residues than rituximab binds in this region (see page 811, “New CD20 mAbs with overlapping, but distinct epitopes,” see also page 815-16 bridging paragraph). More particularly, Meyer teaches the newly created anti-CD20 mAbs m1 and m2 were found to bind within but also in the vicinity of the rituximab binding site (m1 and m2) and elsewhere (m2):“detailed epitope mapping was performed for both mIgG2c-CD20 mAbs m1 and m2, by using PepScan technology. We identified the critical residues of m1 to be 168EPANPSEK175 by using linear (Figure $2A) and circular (Fig 2C, left) peptides with a positional amino acid scan covering the larger extracellular loop. Also for m2, a signal decrease below the WT binding signal occurred within the 1683EPANPSEK175 sequence motif but the binding signal to the linear (Figure S$2B) and circular (Fig 2C, right) peptide was rather low. This suggests that the epitope of both mAbs is located on the larger loop in the same region, however their binding characteristics are different. The data suggests that m1 binds a linear epitope, whereas m2 binds to a conformational epitope.” (see ibid).
Moreover, while these antibodies of Meyers bind within or nearby the rituximab 170ANPS173 epitope they do so with heavy and light chain CDRs non-homologous to those of rituximab.
The art establishes that even if multiple antibodies bind epitopes within the same small region of a given polypeptide, it is not uncommon for said antibodies to bind to different amino acid residues even within said small region and for said antibodies to have dissimilar CDRs.
The above cited evidence establishes the unpredictability in the art; one cannot readily visualize or recognize the identities of the members of the claimed genus that would be encompassed by the claim and possess both the required functional and structural characteristics claimed. Applicant was not in possession of all binders as claimed capable of the recited binding function. The characteristics defining the genus of binder are unknown as the recited language sets forth only what the binders do and now what they are. There is no disclosure of partial structure or other common structural feature, common to the members of the claimed genus encompassed by the claim, which are responsible for the recited/required function.
Recent court cases have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See AbbVie Deutschland GmbH y. Janssen Biotech. Inc. as well as Amgen v. Sanofi, as discussed above. Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it.
Additionally, although the claims recite a process for obtaining the binder, namely “wherein the binder is obtainable by a process comprising: fusing activated B-cells from a mammal previously immunized with a peptide that has a fragment of pro-neurotensin (SEQ ID NO. 5) with cells of a myeloma cell line, screening for cultures of said fused cells that comprises a pro-neurotensin (SEQ ID NO. 5) specific binder” (claim 1), such limitations are not sufficient to establish possession of the entire claimed genus, for example one cannot visualize the structure of every antibody/binder encompassed, including those not yet produced/obtained.
While it is within the skill level of the ordinary artisan to make and screen for antibodies having the claimed functional properties, one cannot envision their structure. Rather, the fact that screening would be necessary to determine which binders result in the desired functional ability (necessary in order to determine whether an antibody falls within the scope of the claim) is further evidence that the genus is not adequately described such to convey possession.
Screening amounts to only a plan for identifying the claimed antibodies, and is not a description of the antibodies themselves. Similarly, it was held in the University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004) that the disclosure of "assays for screening compounds, including peptides, polynucleotides, and small organic molecules to identify those that inhibit the expression or activity of the PGHS-2 gene product," did not satisfy the written description requirement for claims requiring administration of a "compound that selectively inhibits PGHS-2"). See also, Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company, 598 F.3d 1336, 1344 (Fed. Cir. 2010) (recognizing distinction between requirements for written description and enablement), and Centocor, 636 F.3d 1350 ("The fact that a fully-human antibody could be made does not suffice to show that the inventors ... possessed such an antibody.").
A biomolecule defined solely by its ability to perform a function, such as to serve as an antigen recognizing construct, without a known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. See MPEP 2163.
For all of these reasons, the specification fails to convey evidence of possession of the entire genus of antibodies (as at claims 1, 24 and 31).
Allowable Subject Matter
Claims 1, 7-10, 12-13 and 23-37 would be allowable if rewritten or amended to overcome the rejection(s) under 35 U.S.C. 112(a), set forth in this Office action. The prior art of record does not teach nor fairly suggest preparing a sample comprising: bodily fluid from a female subject that does not suffer from cancer, wherein the bodily fluid from said female subject was obtained while the subject was fasting and wherein said female subject has never been diagnosed with cancer at the time the sample of bodily fluid was taken from said female subject, and pro-neurotensin 1-117 (SEQ ID NO: 5) wherein the level of the pro-neurotensin 1-117 (SEQ ID NO: 5) bound to the antibody in the sample, is above 125 pmol/l.
Response to Arguments
Applicant's arguments filed 04/17/26 have been fully considered but they are not persuasive.
112(a) Written Description:
Applicant argues that there is sufficient structure recited in the claims for the structural element of pro-neurotensin 1-117 (SEQ ID NO: 5).
This argument is not found persuasive because the instant written description is not directed to the pro-neurotensin but rather to the genus of antibodies which must possess the unique capability of specifically binding to the pro-neurotensin 1-117 (SEQ ID NO: 5).
Applicant argues that the claims define the antibody by reference to its manufacturing process, which is a recognized and permissible approach where the product cannot otherwise be adequately described. In the case of In re Thorpe, 777 F.2d 695 (Fed. Cir. 1985), the court ruled that product-by-process claims are valid if the process confers distinctive features on the product. Here, the immunization and selection steps ensure specificity for pro-neurotensin 1-117.
This argument is not found persuasive because the issue is not that the product (i.e., the antibody) that is used in the claimed method (the method or preparing a sample) is recited in terms of product-by-process language, rather the issue is still that the product (antibody) still is not sufficiently described in such a way that one having ordinary skill can readily visualize Applicant was in possession of the entire broad genus of antibodies including monoclonal, polyclonal, antibody fragments etc recited in the claim. Even when the antibody is described by the how it is made (namely by the product-by-process limitations) and in terms of its function (i.e., its functional ability, namely it's binding), without a known or disclosed correlation between that functional ability and the structure, there is insufficient description to support possession. In the present case, the product-by-process language describing the product, namely describing how the antibody is made, is merely providing the manner in which the antibodies may be discovered (an assay for screening to identify some antibody binders that fall within the scope). Such limitations do nothing to predict or suggest any particular structure specific to the antibody itself. One of skill in the art cannot simply use any commercially available antibody as the binder in the present claims, rather one must screen and locate those which fall within the scope of the claims. At best the product-by-process limitations merely predict function, which as discussed in the rejection , function alone is not sufficient written description.
Applicant notes in the final sentence on page 3: "For example, in the case of antibodies obtained from hybridomas, each hybridoma produced will yield a specific antibody, with no two having the same sequence." Therefore, the product-by-process claim defines the manufacture of the antibody in a manner that is sufficiently specific to result in a unique antibody specific for pro-neurotensin 1-117. Clearly the rule of In re Thorpe applies. Applicant states that this case is not like the cited Amgen case where the Supreme Court considered broad generic claims to antibodies defined solely by functional characteristics - namely, binding to a specific epitope and blocking PCSK9 - without sufficient structural guidance to enable a person skilled in the art to manufacture and use the full scope of the claimed class without unduly extensive experimentation. The Court emphasized that the disputed patents merely constituted a 'roadmap' and invited extensive trial-and-error screening among potentially millions of antibodies, which was insufficient to satisfy the inventiveness requirement under 35 U.S.C. §112. Applicant further states the claims at issue do not seek to monopolise an open functional class of antibodies. Rather, they are based on specific, reproducible antibody products defined not only by their function but also by their method of manufacture, in particular by production using hybridoma technology which even the Office Action agrees yields "a specific antibody, with no two having the same sequence." Applicant also states that these antibodies produced by hybridoma technology do not constitute an indeterminate functional class. Each hybridoma yields a single, structurally defined monoclonal antibody that is reproducibly obtainable and biologically distinguishable.
These arguments and statements are not found persuasive because the In re Thorpe case is not germane to the instantly recited claims because in In re Thorpe the claims were solely directed to a product-by-process and as shown in the case of In re Pilkington, 411 F.2d 1345, 1348, 162 USPQ 145, 147 (CCPA 1969) the patentability of a product does not depend on its method of production. The issue with the instant claims is that the product (antibody) still is not sufficiently described in such a way that one having ordinary skill can readily visualize Applicant was in possession of the entire broad genus of antibodies including monoclonal, polyclonal, antibody fragments etc recited in the claim.
Conclusion
No claims are allowed.
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/GARY COUNTS/ Primary Examiner, Art Unit 1678
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