DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The present application is a continuation of application 15/641,436, filed 07/05/2017, which is a continuation of 14/432,808, filed 04/01/2015 (Patent No. 9,702,876), which was filed as a proper National Stage (371) entry of PCT Application No. PCT/EP2013/070471, filed 10/01/2013.
Status of the Claims
Claims 21, 24-27, 29-30, 34-35, 37-38, 42-43, 45-47 and 49-50 are pending; claims 1-20, 22-23, 28, 31-33, 36, 39-41, 44 and 48 are canceled; claims 24, 25, 42, 43 and 45-47 are withdrawn; claims 21, 24-27, 29, 30, 34-35, 37, 38, 42, 43, 45-47, 49 and 50 are amended. Claims 21, 26, 27, 29-30, 34, 35, 37, 38, 49 and 50 are examined.
Information Disclosure Statement
The information disclosure statement (IDS) entered 05/27/2026 is considered, initialed and is attached hereto.
Withdrawn Objections/Rejections
The previous objection to the drawings is withdrawn in response to Applicant’s drawings provided in black and white (05/07/2026).
The previous objections to the claims are withdrawn in response to Applicant’s amendments to the claims. Specifically, upon reconsideration the objection regarding the language “in which the amino acid sequence is provided with an additional N-terminal cysteine residue” is withdrawn.
The previous rejections of claims under 35 U.S.C. 112(b) (except for parenthesis in the claims at claims 21 and 46, and see amended rejection below for claim 38) are withdrawn in response to Applicant’s amendments to the claims.
Claim Objections
Claims 27, 29 and 37 are objected to because of the following informalities:
Claim 27 recites “more than once” and “at least two different times”, which appears to be two ways of saying the same thing. It appears that Applicant may have intended to omit “more than once” for “at least two different times, and that this may be a typographical error.
Claim 29 recites “stratified into a risk groups”, the claim appears to contain a grammatical error, namely “groups” is recited as plural and should be singular, i.e., “into a risk group".
Claim 37 recites “stratifying the female subject into risk groups”, it appears that Applicant intended to recite “into a risk group” rather than into multiple groups, plural.
Appropriate correction is required.
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.
New Matter
Claims 27 and 38 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.
Claim 27 recites “performed more than once at least two different times wherein the different times are separated by at least 24 hours”, however, there does not appear to be support in the originally filed specification for two time points “separated by at least 24 hours” as claimed. Applicant has not indicated in remarks support for this amendment.
Claim 38 depends from 37, and 37 recites a method comprising steps of measuring the biomarker, and an optional step of stratifying the subject into a risk group. The language “risk group” appears to encompass risk of future cancer (i.e., not a diagnosis, but an indication of risk). Claim 38 recites “a group that is treated with opioid growth factor (OGF) therapy”, however, the originally filed specification fails to recite support for stratifying a subject into a risk group (an indication of future risk) where those at risk are subjected to treatment/treated with OGF therapy (no support for a group at risk of future disease, who are treated with OGF therapy). The specification appears only to provide support for methods to monitor risk or to monitor the course of treatment (i.e., treating those with disease, not those at risk of disease).
Written Description
Claims 21, 26, 27, 29-30, 34, 35, 37, 38 and 49 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.
Claim 21 recites antibody or fragments of antibodies that bind to Pro-Enkephalin, SEQ ID NO. 1 or one or more fragments thereof, the antibodies binding fragments (the claim encompassed fragments) selected from SEQ ID Nos. 2, 5, 6, 8, 9, 10 or 11, and each of SEQ ID Nos. 2, 5, 6, 8, 9, 10 and 11 are smaller fragments of the Pro-Enkephalin sequence of SEQ ID NO. 1, therefore in reference to antibodies that binds the claimed fragments, the claimed antibody is described only in terms of function rather than structure (must be capable of binding to the specific claimed one or more fragments, not merely any antibody that binds the larger full sequence, the claims providing structure for the fragment to which the antibody binds which does nothing to describe the structure of the claimed antibody).
Claim 35 similarly recites first and second binder (i.e., broader in scope than claim 21 in that binder is not limited to antibody), the binders also described in terms of their function, i.e., what they bind (first binder binds to a region of SEQ ID No. 1 that is within amino acid sequence 133-140, namely SEQ ID NO. 22, second binder binds within SEQ ID NO. 23, wherein each of the regions comprise at least 4 or 5 amino acids).
Regarding claims 21, 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 encompassed by the genus which describes the antibody only in terms of what it binds to, each species potentially binding one or multiple different fragments as claimed, each characterized by a potentially different antibody sequence. Specifically, knowing the sequence to which an antibody binds does not indicate or predict the sequence of the antibody itself.
Even though the claims are limited to antibodies or fragments of antibodies that bind to specific sequences (for example, fragments, or in the case of claim 35, antibodies that binds residues within the claimed sequences), 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 one or more specifically claimed analyte fragments as claimed (the antibodies/fragments are described only in terms of what they bind, i.e. the antigens to which they bind, rather than structure specific to the antibodies/fragments themselves), and the claims are not limited to any particular antibody producing hybridoma cell line(s) or antibody species. The recited claim language attempts to place limitations on the antibodies (referring to antibodies that bind one or more fragments as claimed) by what they do, and as a result places no limitations on the sequences/structure of the antibodies themselves.
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 (or in the case of claim 35 for example, binder) 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 antibodies or fragments of antibodies (binders that are antibodies), one cannot readily visualize the structure(s) of the antibodies themselves that would be encompassed by the recited claims from the claimed limitations. Without some identified structure (specific to the antibodies themselves), one cannot readily distinguish between those antibodies encompassed by the recited language, from those excluded from the claim. The claims do not merely require any pro-enkephalin antibody, but rather specific antibodies which the recited functional ability (referring to binding of the specific fragments). One having ordinary skill, with regard to antibodies that bind the specific smaller claimed fragments of SEQ ID NO. 1, cannot readily visualize what anti-enkephalin antibodies exhibit the desired binding function, and bind one or more of the claimed fragments from those known anti-pro-enkephalin antibodies that do not bind these fragments.
See also independent claim 35, which recites “a first and second binder, wherein the first binder binds to a region of Pro-Enkephalin (SEQ ID NO. 1) that is within amino acid sequence 133-140 (LKELLETG, SEQ ID NO. 22), and the second binder binds to a region of Pro-Enkephalin (SEQ ID NO. 1) that is within amino acid sequences 152-159 (SDNEEEVS, SEQ ID NO. 23), wherein each of said regions comprises at least 4 or 5 amino acids”, the claim (similarly as reasoned above), recites “binders” for the first and second binders in terms of function rather than structure. Further, claims 49 and 50 each recite “binder that binds to the amino acid sequence of SEQ ID NO. 6”.
The originally filed specification fails to identify any particular species reading on the claimed genera (antibodies, or binders).
“[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).
However, in the present case, there is insufficient evidence of such an established structure-function correlation in the case of binders or antibodies or fragments of antibodies, for example, that bind the very specific fragments identified by the claimed SEQ ID Nos., one having ordinary skill in the art cannot readily visualize what structures (what specific antibody sequences) achieve the claimed function.
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 genera of binders or antibodies (or antibody fragments) having the recited functional properties (antibodies that bind one or more fragments selected from SEQ ID Nos. 2, 5, 6, 8, 9, 10 and 11, as at claim 21, or further first and second binders as recited at claim 35, which a first binder binds residues 133-140, SEQ ID NO. 2, the second binder binds residues 152-159, SEQ ID No. 23). Not all of the claimed fragments (SEQ ID Nos. 2, 5, 6, 8-11, referring to claim 21), for example, are overlapping sequences, some of the claimed fragments are from completely different regions of the larger pro-enkephalin protein. The point being, even aside from not knowing the structure of antibodies encompassed by the claims, the claims also encompass several different antibodies in terms of their binding ability (antibodies encompassed by the claimed genus do not even share the same functional ability, rather the claims encompass multiple different antibodies of distinct functional ability).
There is substantial variability in the genus. Since there is 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) (IDS entered 09/29/2022) 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) (IDS entered 09/29/2022), 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) (IDS entered 09/09/2022) 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 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) (IDS entered 09/29/2022). 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 (distinct) antibodies bind epitopes within the same small region of a given polypeptide (overlapping region), 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 antibodies/fragments (or 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 antibodies do and not 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 (referenced previously above).
While it is within the skill level of the ordinary artisan to make and screen for antibodies having the claimed functional properties, one cannot predict their structure. Rather, the fact that screening would be necessary to determine which binders or antibodies 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.
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.
Further, although claim 21 is amended (referring to limitations of previous claim 48 for example) and now recites a process for obtaining the antibodies as claimed, 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.
For all of these reasons, the specification fails to convey evidence of possession of the entire genus of antibodies/antibody fragments as claimed.
Enablement
Claims 21, 26, 27, 29, 30, 34, 49 and 50 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claims 21 and 49 as amended recite methods comprising “obtaining a sample…from a female subject that does not suffer from breast or lung cancer wherein, at the time said bodily fluid was taken from the female subject, said female subject had never had a history of diagnosis of breast or lung cancer, and/or wherein the female subject has an enhanced risk of developing lung and/or breast cancer within 15 years of when said serum or plasma sample was taken” the claim further reciting “wherein enhanced risk…within 15 years… is defined as being greater than three times the risk compared to a female subject with an amount of labelled second antibody or second antibody fragment bound to the complex on said solid phase which is above 40.4 pmol/l”.
As amended, the claims still appear to encompass the action of predicting risk of future breast and/or lung cancer within 15 years in a female subject of any age based on their measured level of pro-enkephalin or one or more fragments thereof (the claims still rely on the correlation of the indicated marker(s) and one’s risk of future cancer that is breast and/or lung, i.e., breast, lung, or both; the claim limit the selected subject on which the method is performed, to these subjects that exhibit the level relative to the claimed threshold).
Referring to the originally filed specification at para [0007], Applicant reports measuring stable fragments of PENK in fasting plasma in the Swedish prospective cohort study (Mamo Diet and Cancer Study, and related baseline level of this biomarker (referring to PENK) to breast-cancer incidence during a 15 year follow up.
See specifically at the Examples, Applicant’s Population Study (starting at para [0100]). PENK in fasting plasma was measured from 2559 female participants of the population, aged 58+/-6 years Applicant reports using multivariable adjusted Cox proportional hazards models to relate baseline PENK to the time to the first event of each of the studied endpoints during a median follow-up time of more than 12 years (para [0100]). Applicant reports the mean value among the population was 47.2 pmol/L, with a standard deviation of 1.2 pmol/L, with the lowest concentration at 9pmol/L (see at para [0103] of the PG Publication).
At Table 6 Applicant refers to their assessment of PENK and breast cancer, Applicant report in a full adjusted model each SD increase of PENK was associated with 28.6% risk reduction or each SD of decrease of PENK was associated with a 40% increased risk of future breast cancer (referring to Table 5). Applicant is using a multivariate Cox proportional hazards model with quartiles to analyze the outcome (prediction of risk of breast cancer) by categorizing a continuous variable (log-transformed PENK) into four groups and assessing its relationship with a time-to-event outcome (assessing both occurrence and time until an outcome).
Figure 3 of the original disclosure represents a Kaplan Meier graph, illustrating the cumulative breast cancer diagnosis in women Quartile 1-4, Applicant reports decreased PENK correlates with a long term increased risk of breast cancer development, women from Q1 having a 3.6 times higher risk to develop breast cancer than women from Q4.
However, this data does not appear to be extend, for example, to women younger than the age as reported in the study (age is already reported as 58 +/-6 years, see as noted above), and further doesn’t extend to predicting risk of any cancer (inclusive of lung cancer as encompassed by the claims), in any aged woman.
Also, notably none of the working examples in the present application are directed to the prediction of risk of other cancer (other than breast cancer), such as lung cancer (as is broadly encompassed by the recited claim language).
Regarding the state of the prior art and further the level of predictability in the art, proenkephalin and its fragments were diagnostically recognized biomarkers, known present and at detectable levels in normal (healthy subjects) and associated with many diseases (other than just increased risk of cancer, such as breast or lung), detectable samples including blood, plasma or CSF, see for example, EP2293079A2 (Bergmann and Ernst, abstract, and paras [0001] [0002], [0005]-[0016], reference teaching that proenkephalin can be used to diagnose a variety of diseases comprising diseases/ disorders of the central nervous system, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemia comprising myocardiac ischemia, schizophrenia, diseases/ disorders of the immune system; diseases/conditions of pain, chronic pain, migraine, tension type headache, tumor diseases/ cancer comprising lymphoblastic leukemia, malignant brain tumors, adenomas, in particular human pituitary adenomas, disorders of the blood brain barrier, multiple sclerosis, inflammation, chronic arthritis, infectious diseases, bacterial and viral infections, in particular infections of Gram-positive bacteria, boma disease virus infections, peritonitis, intoxication, AIDS, stress, trauma comprising head trauma, infarction, in particular cerebral infarction, heart and cardiovascular diseases comprising coronary heart disease, bone and skin disorders, malaria, chronic/ obstructive pulmonary disease and cerebral damage). See Bergmann and Ernst at para [0009], who report the level of proenkephalin is altered in body fluids and tissue in a variety of diseases, e.g., increased compared to healthy control subjects in patients with brain infarctus in the acute phase, and diabetes patients with symptomatic myocardiac ischemia. See also at para [0009], reporting significantly increased levels in those suffering from migraine and headache, and associated also with schizophrenia patients.
At para [0010] Bergmann and Ernst report decreased levels in those patients with Parkinson’s disease compared to healthy control subjects, further para [0011], decreased levels known to associate with Huntington’s disease, as a few examples.
See also Bergmann et al., US PG Pub No. 2008/0261232A1 (IDS entered 09/29/22), which teaches (para [0081]), decrease of enkephalin-fp concentration detected in 75% of patients with inflammatory bowel disease, like Crohn’s disease or colitis ulcerosa (ENK-fp referring to enkephalin-footprint, namely residues 119-159 (Bergmann 2008, para [0022]-[0023], which corresponds to Applicant’s elected species presently, SEQ ID No. 6).
Further regarding the state of the prior art, it appears that little was known in the art at the time regarding the claimed marker and its fragments particularly related to breast cancer, or a prediction of future development of cancer, such as breast cancer.
As discussed in detail previously above, Applicant’s working examples relied on multivariate analysis, Applicant’s predictive models do not appear to solely rely on the biomarker level (rather, see as noted above PG Pub para [0100], used multivariable adjusted model, all traditional cardiovascular risk factors, and in analyses of cancer also heredity for cancer). Whereas the working examples are narrow with respect to patient population (in terms of age, for example), timeline of future prediction (endpoints of the study), sample (serum), type of cancer (limited to breast), and the predictive analysis model, as a few examples, the claims are much broader in scope. Even further, see for example independent claims 21 and 49, the claim encompasses measuring the level (of proenkephalin, or fragments thereof as claimed) and correlating the level with a subject’s risk of getting cancer (breast or lung) (i.e., the subject on which the method is performed is a subject that never had a history of diagnosis of breast or lung cancer, and/or wherein the female subject has an enhanced risk of developing within 15 years of when the sample was take, those at enhanced risk defined by the claims as those with measured levels 3X above 40.4 pmol/l). The claims still encompass determining future risk based on the elevated marker level.
The level of ordinary skill in this art is high, as the invention is related to clinical diagnostics/diagnostic biomarker assay detection and statistical multivariate analyses.
The data and specification provide insufficient guidance for how to make and use the claimed invention when contrasted with the extremely broad scope of the claims. The data do not show how to make or use the claimed invention. For example, there is a lack of direction or guidance regarding how to use the claimed invention to predict/indicate a subject is a subject at future risk of developing cancer, that is breast cancer, based merely on measuring the level PENK that is SEQ ID NO. 1 as claimed, or one of the fragment sequences as claimed. Additionally, the method reported in the working examples indicates measuring pro-enkephalin, the population study does not specify any specific fragments as detected/correlating with predicted risk of future cancer, such as breast cancer.
Although claim 37 does further recite “wherein a reduced level of Pro-Enkephalin (SEQ ID NO. 1), or of said one or more fragments thereof is predictive for an enhanced risk of getting breast cancer or lung cancer in comparison to a normal female subject”, see as discussed above, the working example is much broader in scope, for example Applicant’s data takes into consideration other risk factors/variables, Applicant is not relying merely on measured PENK and further, measuring a decreased level in a patients sample could be indicative of other disease, e.g., inflammatory bowel disease, as discussed in detail previously above).
As noted previously, PENK has been known in the art to increase/decrease expression in relation to a variety of different diagnosis in a variety of sample types. Applicant’s disclosure does not specifically or clearly link PENK with any female (as is encompassed by the recited language) subject’s future risk of cancer, such as breast cancer as elected.
Claim 50, although reciting broader claim language, also encompasses/is directed to indicating risk of breast or lung cancer based on a level lower than a threshold level for pro-enkephalin of SEQ ID NO. 6 (see specifically, as the claims recites subjecting to measures for prevention based on the measured level relative to the indicated threshold, preventive measures indicates the subject is at risk of breast or lung cancer). The reasoning applied above regarding claims 21 and 49, also apply presently.
For all of these reasons, Applicant’s originally filed specification fails to support enablement, as there is insufficient description as to how to make and use the invention as claimed, without undue experimentation.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21, 26, 27, 29-30, 34, 35, 37, 38, 49 and 50 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.
Claims 21 and 46 recites at step c) parenthesis in the claims, namely “Pro-Enkephalin (SEQ ID NO.1)”. Parenthesis in the claims raises question as to what is actually required by the claim. For example, when limitations are recited within parenthesis it is not readily clear if the claims are limited to that which is recited in the parenthesis, or rather if the limitations within the parenthesis are merely exemplary. As a result, the claims are considered indefinite because the boundaries of what is encompassed by the recited language is not readily clear.
Claim 38 recites “said method female subject is stratified into a group that is treated with opioid growth factor (OGF) therapy”, however the recited language is indefinite because it is unclear if the recited limitation is a step performed as part of the method, or if the claim limitation is describing that the method is performed on those subjects stratified before the method (the method is performed on those stratified into a group that is treated). Based on earlier claim language and interpretations, as well as the originally filed specification, it appears that it is Applicant’s intention that the limitations of claim 38 be recited to be performed as part of (as a result of) performing the claimed method, i.e., as an additional active step. However, the amended language fails to clearly indicate whether or not this is an active step of the instant method, or a limitation describing the subject population on which the method is performed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 21, 26-27, 29, 30, 34, 37-38, and 49-50 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and to laws of nature/natural phenomena without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Claims 21, 49, 50 the claims encompass measuring the level of Pro-enkephalin, SEQ ID No. 1, or one or more fragments thereof, in a sample of bodily fluid and correlating said level with risk of getting breast cancer or lung cancer/predicting risk of breast and/or lung cancer, wherein a reduced level…is predictive for an enhanced risk of getting breast cancer or lung cancer in comparison to a normal female subject.
The natural relationship to which the claims are directed (i.e., the relation between Pro-enkephalin, or fragments thereof, and further Pro Neurotensin levels (see for example, dependent claim 30) and risk/enhanced risk of future breast cancer (Applicant’s elected species) or lung cancer) is a law of nature (see as noted above, claims 21, 30, 34). Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The present claims are similar to those in Mayo because they involve a “relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of the biomarker(s) and future risk of disease. The correlation is a judicial exception because it exists in principle apart from any human action” (id. at 77). Further, as a result, the correlation itself cannot form the basis for eligibility.
Claims 21, 30, 37, 49 and 50 each recite limitations that amount to comparing/comparison with a threshold/cutoff concentration. Comparing a sample to a control or target data/subject/population is further categorized as an abstract idea, namely mental process/concept performed in the human mind (such as a practitioner simply thinking about the measured level of the biomarker(s) in relation, and making an evaluation, judgment or opinion, i.e., indicating subject at risk). The claims, under reasonable broadest interpretation, cover performance of identifying risk solely within the human mind.
Similar concepts involving comparing information regarding a sample or test subject to a control or target data have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo).
Claim 34, limits the fragment to MR-Pro-enkephalin (SEQ ID NO. 6), Applicant’s elected species, which this limitation merely further narrows the naturally occurring biomarker that correlates with risk.
Claims 29, 37 and 38 recite limitations directed to stratifying the subject into risk groups, the act of stratifying into risk groups amounts to mental process/concept, as it amounts to making an observation and forming a judgment/opinion.
Step 2A, Prong 2
The above discussed limitations directed to the natural correlation and to the abstract ideas are themselves the judicial exceptions, and as such are not sufficient to integration the judicial exceptions into a practical application thereof.
Regarding the claims, in addition to the judicial exceptions noted above, claims as amended further recite that the subject at the time the sample was taken is a “female subject” that had never “had a history of diagnosis of breast or lung cancer…”. These limitations further narrow the judicial exception (by narrowing the subject on which the method is performed), however, do not further apply, rely on or use the judicial exception in such a way to amount to integration into a practical application.
Claim 21 further recite limitations that further narrow the immunoassay relied upon in the measuring step, see “bringing a serum or plasma sample… into a contact with a solid phase comprising a bound first antibody or first antibody fragment that binds to Pro-Enkephalin SEQ ID No. 1 or said one or more fragments thereof… react with said bound first antibody or antibody fragment to form a complex bound to said solid phase”, “contacting said solid phase with the bound complex with a second antibody or second antibody fragment, wherein said second antibody fragment is labelled with a detectable label”, c) “measuring the level of Pro-Enkephalin (SEQ ID No. 1) or said one or more fragments in said sample by measuring the amount of labelled second antibody or second antibody fragment bound to the complex on said solid phase”. However, such immunoassay steps are insufficient to integrate the judicial exception(s) because their purpose is merely to obtain data. These limitations do not go beyond insignificant presolution activity, these are data gathering steps necessary in order to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). These steps are recited at a high level of generality and are not tied, for example, to any particular machine or apparatus.
Similarly, none of the other independent (or further dependent) claims recite steps/elements which further amount to integration into a practical application (none further apply, rely on, or use the judicial exception in a sufficient and meaningful way as to amount to an integration).
Although claim 38 does recite “wherein said subject is stratified into a group that is treated with opioid growth factor (OGF) therapy”, this limitation does not amount to integration of the judicial exception into practical application. For example, although this claim references a specific therapy, the claim recites language that does not clearly amount to administering therapy to those subjects as a result of the judicial exception(s). The claim does not clearly link and apply a treatment step with the correlation, for example, the claim does not recite steps that amount to administering OGF therapy to a female subject who is determined to be at (future) risk of breast cancer.
Notably claims 49 and 50 do recites steps/elements which amount to treatment, see for example, at claim 49 “subjecting said female subject to measures for preventing breast cancer or lung cancer, or subjecting said female subject to measures for treating breast cancer or lung cancer” (and claim 50, “subjecting a female subject to measures for preventing breast cancer or lung cancer”). Limitations directed to “treatment” can integrate a judicial exception into a practical application thereof, however, when evaluating these limitations, it is necessary to consider the particularity or generality of the treatment limitation, whether these limitations have more than nominal or insignificant relationship to the exception(s), and whether they are merely extra-solution activity or field of use. In the present case, the limitation “subjecting… to measures for preventing breast cancer or lung cancer” are not particular, rather this limitation is extremely general. The recited treatment amounts to insignificant post-solution activity, namely merely applying treatment (generally) in response to determination of risk.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Further, the claimed steps/elements recited in addition to the judicial exceptions themselves also fail to amount to significantly more than the judicial exceptions.
For example, regarding immunoassay to detect pro-enkephalin, particularly Applicant’s elected species of SEQ ID NO. 6, see Ernst et al., EP 2293079A2 (IDS entered 09/29/2022). Ernst teach at Example 5 or para [0038], a method comprising the steps of merely obtaining a sample of bodily fluid from a subject (subjects generally, i.e., not limited to a particular sex, therefore interpreted as encompassing male and female), including healthy subjects (those not suffering from breast or lung cancer), and adding to said sample a binder (antibody binding reagents) that form a complex with a fragment of SEQ ID NO. 1, namely that bind with the fragment of SEQ ID NO. 6 (i.e., antibody that binds an epitope in SEQ ID NO. 6 would bind and form complex with SEQ ID NO. 6, Applicant’s elected species).
See also Ernst et al., Proenkephalin A 119-159, a stable proenkephalin A precursor fragment identified in human circulation, Peptides, 27, (2006), p. 1835-1840 (IDS entered 09/29/2022), specifically also discloses a solid phase, double antibody immunoassay that specifically binds and detects SEQ ID NO. 6 as claimed (see for example, Ersnt 2006 at Figure 1).
See as discussed above, claims 49 and 50 do recite treating a subject, however, for the reasons as discussed above, these treatment limitations amount to no more than insignificant post-solution activity. The treatment limitations, as noted in detail above, are recited at an extremely high level of generality.
Appending a generic, routine, and obvious post-solution treatment step does not provide a sufficient inventive concept to satisfy § 101. As was the case in Mayo and Ariosa, the method claims at issue here amount to "nothing significantly more than an instruction to doctors to apply the applicable laws when treating their patients" using "conventional steps, specified at a high level of generality." Mayo, 132 S. Ct. at 1298, 1300; Ariosa, 788 F.3d at 1377-78.
Regarding the ordered combination, there is also no evidence of record to indicate that the additional elements, alone or in combination, go beyond that which is well-known, routine and conventional activity. Broadly or generically treating is tantamount to a mere instruction to “apply” the judicial exception using well-understood, routine or conventional techniques in the field. It does not go beyond general instructions to apply or use the judicial exception.
For all of these reasons, the claims are rejected under 35 U.S.C. 101.
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.
Claims 21, 26, 29-30, 34, 35, 37, 49 and 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,702,876B2 in view of Ernst et al., EP 2293079A1 (cited previously above), Buechler et al., US 5,939,272, Buechler et al., US PG Pub No. 2004/0121343 and Nieuwenhuizen US Patent 5,124,439. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Regarding claim 21, see ‘876 similarly recites a method (performed on a person at risk of getting breast cancer (applicant’s elected species) and lung cancer, the method comprising measuring the level of proenkephalin or fragments thereof (‘876 similarly teaching level of SEQ ID Nos. 1, 2, 5, 6, 8, 9, 10 or 11, as claimed, see ‘876 at claim 1), and correlating with risk of getting as claimed (see ‘876, claim 1, in a person that does not suffer from cancer, which encompasses the claimed subject population), further see ‘876 recites measuring by immunoassay comprising the steps as claimed (claimed steps a-c, see ‘876 at claim 1).
See ‘876 at claim 1 does teach a reduced level below 100 pmol/l, however, fails to teach a level below 40.4pmol/l.
‘876 does teach antibodies or fragments of antibodies that bind to the claimed fragments, however, fails to teach the antibodies prepared by immunizing a mouse with a peptide-BSA conjugate as claimed, fusing splenocytes obtained form the immunized mouse, and producing said antibodies or antibody fragments from the resultant fused cells.
Ernst et al., similarly to ‘876, teach methods detecting proenkephalin, specifically teaching antibodies that bind with regions within the fragment of Applicant’s elected species, namely SEQ ID No. 6. See at Example 5 or para [0038], a method comprising the steps of merely obtaining a sample of bodily fluid from a subject (subjects generally, i.e., not limited to a particular sex, therefore interpreted as encompassing male and female), including healthy subjects (those not suffering from breast or lung cancer), and adding to said sample a binder (antibody binding reagents) that form a complex with a fragment of SEQ ID NO. 1, namely that bind with the fragment of SEQ ID NO. 6 (i.e., antibody that binds an epitope in SEQ ID NO. 6 would bind and form complex with SEQ ID NO. 6, Applicant’s elected species).
Ernst teach healthy subjects as having levels below 109 pg/ml (para [0046]), See further figure 6 demonstrating the frequency distribution of ENK-fp (corresponding to the region presently claimed as SEQ ID NO. 6) concentration in plasma controls, 95% of those healthy subjects showed between 40-100 pmol/l (see for example, Example 6, para [0068], between 40-100 pmol/l).
Buechler et al. (US 5,939,272) teach threshold assays in which a detectable result is observed when the target analyte is present at a concentration greater than a defined cut-off point or threshold concentration (see in particular the abstract; column 1, lines 15-30; column 19, line 23 to column 21, line 18; column 30, line 16 to column 32, line 41). For example, the selected threshold can be the upper limit of a normal range for a target analyte that is elevated under certain conditions (see also column 8, lines 38-46 and line 66 to column 9, line 4; and the claims). Specifically, Buechler teach comparing against a threshold/control data to interpret the measured analyte in terms of providing a diagnostic result (see col. 47, lines 9-14).
Buechler et al. (2004/0121343) also teach that clinical marker may be compared to a “normal” value, or to a value identified as being indicative of the presence or absence of a particular disease (para [0023]). A threshold may be selected, above or below which the test is considered normal or abnormal (para [0024]-[0025], [0054]). Diagnostic and/or prognostic markers are mentioned (para [0029], [0053]). Changing the cutoff selected to distinguish between a positive and negative result trades off between the number of false negatives and positives (i.e., trades off between sensitivity and specificity, paras [0065], [0068], [0112]). See especially at para [0112], where it is taught that one skilled in the art can adjust the diagnostic threshold in order to optimize clinical sensitivity and specificity.
Considering healthy subjects showed levels between 40-100 pmol/l, and ‘876 teach level below 100 pmol/l are at a risk of breast cancer, and further because threshold/cutoff is a considered in the prior art to be a result effective variable, as it impacts sensitivity and specificity, it would have been prima facie obvious to one having ordinary skill in the art to have modified ‘876 in order to have arrived a threshold of 40.4 pmol/l out of routine optimization of experimental conditions, namely by trying threshold/cutoff levels within the prior art disclosed range considered to distinguish those who are healthy from those that are diseased, one motivated to do so in order to determine the optimum ideal cutoff value for achieving desirable sensitivity and specify. One having ordinary skill would have a reasonable expectation of success because it was known between the cited references that levels below 100 pmol/l indicated increased risk, and it was also known that those who are healthy can exhibit levels between 40-100, therefore one would expect success optimizing the cutoff to distinguish between these two populations. Further one would expect success given that the Buechler references recognized cutoff/threshold as an optimizable variable.
Regarding how the claimed antibodies are produced, see Ernst et al., as cited in detail above, Ernst further teach producing antibodies against proenkephalin using methods known in the art, for example by the steps of immunizing mice, fusing splenocytes obtained with myeloma cell line, and producing antibodies (see e.g., Ernst et al. at para [0033]).
See further Nieuwenhuizen as another example of using this technique to produce antibodies, Nieuwenhuizen specifically teach immunizing with BSA-peptide conjugate (see teaching BSA as a carrier protein for this purpose, col. 3, lines 25-27), see specifically col. 6, Example V, immunized with BSA-peptide conjugate).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified ‘876 in order to produce the antibodies with the method as taught by Ernst and further Nieuwenhuizen, as an obvious matter of using a known technique known and employed in the prior art for producing specific antibodies to a peptide antigen (namely, the steps of immunizing, fusing and producing/recovering antibodies). One having ordinary skill in the art would have a reasonable expectation of success using an art recognized technique for its intended purpose.
Regarding claim 26, see ‘876 at claim 5 (determining at least one clinical parameter selected from age, presence of diabetes mellitus, and currently smoking).
Regarding claim 29, see ‘876 at claim 6, stratify into risk groups.
Regarding claim 30, see ‘876 at claim 12 and 13, further measuring pro-neurotensin 1-117, SEQ ID No. 17, correlating with risk, at claim 13, teaching pro-neurotensin or fragments thereof above 78pmol/l.
Regarding claim 34, see ‘876 at claims 1, 9, 12 and 14, fragment is MR-proenkephalin, SEQ ID No. 6.
Regarding claim 35, although not described as a kit, see ‘876 at claims 9 and 18, ‘876 is teaching detection with the same components (same antibody product reagents, together). Therefore, although not recited as a “kit”, ‘876 is teaching a product that is used that is structurally indistinct as that presently recited at claim 35.
Regarding claim 37, see ‘876 as cited above (same analyses as applied at claim 1, and as noted, see ‘876 at claim at claims 9 and 18, teaching detection with antibody, i.e., binders, as claimed).
Regarding claims 49 and 50, see ‘876 at claim 1 as cited previously above.
Response to Arguments
Applicant's arguments filed 05/07/2026 have been fully considered but they are not persuasive for the following reasons.
Regarding remarks at page 10, Applicant indicates amendments to the claims to overcome previous objections. See withdrawn objections/rejections as indicated above.
Regarding the rejection of claims under 35 U.S.C. 101, Applicant argues the claims as amended do not recite any judicial exceptions, and as such rejections are moot. However, these remarks are not persuasive because, although amended to reword limitations previously reciting steps or predicting risk, etc. (such as the limitations directed to the natural correlation and abstract ideas), the claims as a whole still encompass these concepts. For example referring to claim 21 and those that depend from 21, the claims still require the correlation between the biomarker and the subject’s risk (wherein enhanced risk of developing lung and/or breast cancer within 15 years of when said serum or plasma sample was taken is defined as being greater than three times the risk compared to a female subject with an amount of the labelled second antibody or second antibody fragment bound to the complex on said solid phase being above 40.4pmol/l). The claims as a whole encompasses correlating the marker level with determining risk (i.e., the claims are limited to a method performed on those particular subjects that are those subjects having a level that the claims specify is the level indicative of risk).
Regarding remarks to claim 50, Applicant remarks that this claim has merely one active step and so does not recite a natural correlation, however, the claim as a whole encompasses the natural correlation, see referring to the step, the claim recites “subjecting” to “measures for preventing breast or lung cancer”, the method indicating prior to subjecting, sample is obtained, and the subject’s biomarker level is less than the claimed threshold. As a whole, the claim is directed to correlating the biomarker with risk, and applying preventative measures, as preventative measures suggests/implies future risk (i.e. preventing the subject from obtaining the disease/condition). The natural correlation, while not clearly/explicitly stated, it is described in the claim (see MPEP 2106, II. A. (1), regarding prong one consideration).
Regarding the rejection of claims under 35 U.S.C. 112(a), as having insufficient written description (remarks page 11-12), Applicant argues the antibody is claimed in terms of product-by-process limitations, process defining how the product is made and so the rejection should be withdrawn. See remarks page 12, Applicant argues if one follows the process, they obtain the product.
However, this argument is not persuasive, see the MPEP, 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.
Further in response, it is noted that MPEP 2113 states: "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979).
In the present case, the recited process for obtaining the binder does nothing to further elaborate on its structure in a way that would allow one to recognize a structure-function correlation. Put another way, the recited process for making the product does not apply any additional structure (does not provide additional structure/structural elements that can be attributed to the recited binding function that is also claimed, i.e., fails to further describe a structure-function relationship). The claims, at most, are describing the antibody in terms of what/how it binds and how it’s made, and provide no structure specific to the antibody itself. It is noted that it is not disputed that methods of screening for antibodies is known (the present issue is not one of enablement), rather the issue is that Applicant has not provided sufficient description to support possession of the entire genus of antibodies as claimed. Screening amounts to only a plan for identifying the claimed binders, and is not a description of the antibodies themselves.
Regarding remarks specific to the rejection under 35 U.S.C. 112(a), regarding enablement (remarks page 12), Applicant refers to same reasons as above, that one could make and use the claimed invention. However, see response to remarks above, as noted previously the claims still recites/encompass the limitations which raised issue regarding enablement in the previous action.
Regarding remarks at page 13 that the claims are not obvious over US 9,702,876 on the ground of non-statutory double patenting, see the rejection as set forth in detail above, the rejection is maintained for reasons as indicated.
Conclusion
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677
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