Detailed Action
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-6 are pending and under examination on the merits.
Priority
This application is a 371 of PCT/EP2022/053900, filed 02/17/2022, which claims benefit of priority to United Kingdom 2102277.7, filed 02/18/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
IDS
The information disclosure statement (IDS) filed 08/15/2023 has been considered.
Claim Objections
Claims 2-6 are objected to because of the following informalities: recitations of “…Claim 1…” should read “…claim 1…”. Appropriate correction is required.
35 U.S.C. 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 1-6 are rejected under 35 U.S.C. 101, because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim is directed to a judicial exception (natural phenomenon; correlation between the recited binding (detected amount of type VI collagen) and esophageal fibrosis and/or dysphagia and/or likelihood and/or severity of esophageal fibrosis and/or dysphagia). Furthermore the claim does not integrate said judicial exception in to a practical application, and the claim does not recite additional elements that amount to significantly more than said judicial exception.
Where a claim describes a judicial exception, such a claim “requires closer scrutiny for eligibility because of the risk that it will ‘tie-up’ the excepted subject matter and pre-empt others from using [the judicial exception]" (federal register, p.74622, C1). While all inventions to some degree involve natural laws, products, and other judicial exceptions, the new guidance regarding patent eligibility makes clear that a practical application of these exceptions is necessary, offering “significantly more” than the exception itself. Limitations that were found not to be enough to qualify as “significantly more” include:
Mere instructions to implement an abstract idea on a computer;
Adding generic instructions that the judicial exception should be used ("apply it");
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality;
Adding insignificant extra solution activity to the exception ("mere data gathering"); and
Generally linking the use of the exception to a particular technological environment or field of use.
The MPEP (see § 2103-2106.07) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
In the instant case, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because as indicated above, the claims are drawn to a natural correlation.
Claim 1 is directed to a method of immunoassay for detecting and/or monitoring esophageal fibrosis and/or dysphagia in a patient and/or assessing the likelihood of or the severity of esophageal fibrosis and/or dysphagia in a patient, wherein said method comprises: (i) contacting a biofluid sample from a patient with a monoclonal antibody that specifically binds to a C-terminal epitope of the C5 domain of the a3 chain of type VI collagen, (ii) detecting and determining the amount of binding between the monoclonal antibody used in step (i) and peptides in the sample or samples, and (iii) correlating said amount of binding of each monoclonal antibody as determined in step (ii) with values associated with normal healthy subjects and/or values associated with known disease severity and/or values obtained from said patient at a previous time point and/or a predetermined cut-off value. Claim 2 only adds the limitation of the epitope bound. Claim 3 only adds that the antibody does not specifically bind to or recognize the epitope of SEQ ID Nos: 2 or 3. Claim 4 only limits the sample type. Claim 5 only limits the immunoassay type to a competition or sandwich assay. Claim 6 only limits the assay to a radioimmunoassay or an ELISA. Thus, claims 2-6 incorporate and fail to remedy (by integration of addition of significantly more) the deficiency (untransformed judicial exception) of claim 1, from which they depend.
Regarding claim 1, the claim language reciting the judicial exception is found implicitly throughout the claim, but is particularly apparent in step iii.
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A. Here, the instant claim 1 recites, “A method…for ….” Therefore, the instant claim 1 is directed towards a method, which is a process under 35 U.S.C. 101. So the answer to step 1 is “YES.” Thus, the analysis proceeds to Step 2A.
Step 2A - A two-prong analysis. For prong 1, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong 2, which asks whether the claim integrates the judicial exception into a practical application. If “No,” the analysis moves on to step 2B. Here, the instant claim 1 includes step iii directed to a natural phenomenon (correlation), which is a judicial exception. Therefore, the answer to prong 1 of step 2A is “YES.” Thus, the analysis proceeds to prong 2 of step 2A. Here, the instant claim 1, while additionally reciting the additional, generic steps of contacting a biofluid sample with an antibody and detecting the amount of binding, fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional steps of contacting a biofluid sample with an antibody and detecting the amount of binding are recited at a high level of generality conforming to well-known assay types in the art (see for example, Hosseini S et al (Advantages, Disadvantages and Modifications of Conventional ELISA. In: Enzyme-linked Immunosorbent Assay (ELISA). SpringerBriefs in Applied Sciences and Technology (2018). Springer, Singapore. https://doi.org/10.1007/978-981-10-6766-2_5).
For all of these reasons, the steps of contacting a sample and antibody and determining/detecting binding amount to no more than mere data gathering steps and do not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in claim 1 as exemplified by step iii.
Therefore, the answer to prong 2B is “No” and the instant claim 1 is therefore directed toward patent ineligible subject matter under 35 U.S.C. 101 and is therefore rejected under 35 U.S.C. 101.
Claims 2-6, as discussed above, incorporate he judicial exception of claim 1 via dependency. Claims 2-6 fail to add a step (such as a step directed to treatment or prophylaxis) that would integrate the judicial exception into a single practical application. The limitations added in claims 2-6, as discussed above, fail to add significantly more to the exception so as to transform the claim(s) as a whole into patent eligible subject matter.
Therefore, claims 1-6 are rejected under 35 USC §101 as being directed towards a patent ineligible natural phenomenon (a natural correlation), failing to integrate or add significantly more so as to transform the metes and bounds of the claims into subject matter eligible for patentability.
Claim Rejections - 35 USC § 112(a)
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent 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. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims a broad genus of antibodies by impermissibly allowing variation within the CDRs (where there is no recited structure that is required) without disclosure of a conserved structure/representative number of species to adequately describe said genus. The Application discloses 1 example (1 set of 6 CDRs with varied framework regions) of an antibody that performs in the method as claimed and does not provide evidence of other antibodies or variants of the single set of 6 CDRs that would predictably function to bind as claimed. Therefore, in view of this disclosure, Applicant is claiming a broad genus of antibodies without a representative number of species of said genus. The specification does not provide adequate written description for the entire claimed genus of species of antibodies or of CDRs binding the recited portion of type VI collagen as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequence combinations (bearing any mutations or not) might be included in the genus.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has only fully disclosed 1 set of 6 CDRs (1 species) for consideration. Thus, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of only 1 species having 100% identity to the disclosed CDR sequences is not sufficiently representative of the entire genus claimed (encompassing CDRs not described or even invented and/or multiple combinations of mutations in the CDRs).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences that confer upon an antibody the ability to function as claimed because the instant specification does not provide structural antibody features that correlate with a functional ability to bind in the method as claimed.
Absent a clear description of the at least minimal structural features correlating with a functional ability to bind as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied/interchanged such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind type VI collagen. Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind type VI collagen, as claimed. Thus, the claims need to specify exact CDR sequences of the anti-type VI collagen antibody.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed CDR sequences may be combined/mutated such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations, that correlate with the ability to function as claimed, and because the one disclosed species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims require an antibody binding type VI collagen. The specification does not describe which amino acid residues of the antibody are responsible for the functions claimed. Rather, the specification implies that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides disclosure of 1 antibody, it fails to disclose the structures common to all members of the genus of antibodies encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant antibodies and fails to disclose which sequences are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Goel et al (2004, J. Immunol. 173: 7358-7367) teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues (see entire reference).
Khan et al (2014, J. Immunol. 192: 5398-5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “[i]t has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity...Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naive BCR repertoire, because Kaji et al (as cited by Khan et al)....have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs,” (see entire reference of Khan et al).
Poosarla et al (2017, Biotechn. Bioeng. 114(6): 1331 -1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...." (see entire reference.)
Janeway et al (Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The generation of diversity in immunoglobulins. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27140/) teach that, “[v]irtually any substance can elicit an antibody response. Furthermore, the response even to a simple antigen bearing a single antigenic determinant is diverse, comprising many different antibody molecules each with a unique affinity, or binding strength, for the antigen and a subtly different specificity,” (see for example, paragraph 1 of page 1/12).
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Therefore, the antibodies, as claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s).
Furthermore, the genus of epitopes recited in claims 1 and 4-6 is inadequately described. The prior art supports that epitope selection is a critical step in immunoassay design and that said selection is unpredictable. Proteintech (The importance of epitope selection in experimental design, Proteintech, obtained from: https://www.ptglab.com/news/blog/the-importance-of-epitope-selection-in-experimental-design/?srsltid=AfmBOophB0oOURPWVt8-Ev696rJUsE1_yPXsMEFvA57ECk6diMWAmt6D; accessed 02/10/2026) teaches that, when designing an experiment that uses antibodies, one often overlooked parameter is the exact binding site of your antibody on the protein of interest, also known as the epitope. An antibody’s primary role is to bind to a specific protein (also known as the antigen or immunogen) which in turn allows for the detection, neutralization, or modification of the protein’s activity. Carefully choosing your antibodies based on epitope binding site can greatly influence experimental outcomes, therapeutic strategies, and diagnostic accuracy (see for example, paragraph 1 of page 1-13). Additionally, Proteintech teaches that an epitope which functions in one assay method may fail in another) see for example, pages 1/13-2/13). The artisan is effectively invited to screen for epitopes which function in the assay method as claimed due to the absence of description which enables the artisan to readily envisage which members of the recited genus of epitopes would function as claimed.
Therefore, claims 1-6 are deemed to fail to meet the written description requirement, as presently drafted.
Enablement
Claims 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for detecting and/or monitoring eosinophilic esophagitis (EoE) in a patient and/or assessing the likelihood of or the severity of EoE, does not reasonably provide enablement for a method for detecting and/or monitoring esophageal fibrosis and/or dysphagia in a patient and/or assessing the likelihood of or the severity of esophageal fibrosis and/or dysphagia in a patient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.”
These factors include but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
Claims 1-6 are broadly directed to a method for detecting and/or monitoring esophageal fibrosis and/or dysphagia in a patient and/or assessing the likelihood of or the severity of esophageal fibrosis and/or dysphagia in a patient. The method is accomplished by performing an assay comprising steps of contacting a biofluid sample with a monoclonal antibody that specifically binds to a C-terminal epitope of the C5 domain of the a3 chain of type VI collagen, detecting and determining the amount of binding, and correlating said amount of binding with values associated with normal healthy subjects and/or values associated with known disease severity and/or values obtained from said patient at a previous time point and/or a predetermined cut-off value.
The nature of the invention
Claims 1-6 are broadly directed to a method for detecting and/or monitoring esophageal fibrosis and/or dysphagia in a patient and/or assessing the likelihood of or the severity of esophageal fibrosis and/or dysphagia. The claims are directed to biological subject matter which is understood to be complex and often unpredictable.
The state of the prior art
The state of the prior art supports that esophageal fibrosis may be caused by a wide variety of different conditions exhibiting different driving pathological mechanisms and further distinguishes the pathophysiological traits of esophageal fibrosis due to eosinophilic esophagitis (EoE) versus esophageal fibrosis due to other causes (see for example, Ambruster-Lee et al (J Leukoc Biol. 2018;104:31–40)). The state of the prior art supports that dysphagia may be caused by a wide variety of different conditions exhibiting different driving pathological mechanisms and further acknowledges that different causes will respond differently to different treatments (see for example, Mayo Clinic (Dysphagia, obtained from: https://www.mayoclinic.org/diseases-conditions/dysphagia/symptoms-causes/syc-20372028(accessed 02/11/2026)(Pub. 07/31/2024)).
The level of one of ordinary skill
As the claims are directed to a method for detecting and/or monitoring esophageal fibrosis and/or dysphagia in a patient and/or assessing the likelihood of or the severity of esophageal fibrosis and/or dysphagia, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
The art teaches there are many different causes for esophageal fibrosis and dysphagia, where the different causes are driven by divergent pathophysiology (see supra). Ambruster-Lee et al teach that there is no universal treatment for esophageal fibrosis and that there is a subset of patients that do not exhibit a response such that treatment presents a challenge to clinicians (see for example, the abstract at page 31). Likewise, Mayo Clinic teaches that the causes of dysphagia vary, and treatment depends on the cause.
(F) The amount of direction provided by the inventor
Applicant only discloses use of the claimed method using samples from adult patients with EoE (see infra). Applicant does not disclose examples or data for the claimed method as being used for samples taken from patients not having EoE. This does not support or reasonably suggest that application of the claimed method would predictably function for use in any patient other than a patient having EoE where esophageal fibrosis and/or dysphagia are EoE-related. Further, the data provided by Applicant do not show or allow for any comparison of fibrotic and non-fibrotic EoE or for EoE with or lacking dysphagia (such that not showing of a correlation between collagen VI and fibrosis or dysphagia is demonstrated).
The existence of working examples
The only clearly disclosed working example disclosed pertains to use in patients with EoE (see Example 3 at pages 9-10 of the instant specification).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The case is directed to biological subject matter, which is by nature complex. There are no working example provided for use in patients not having EoE and the state of the art fails to step in to provide enablement where the instant disclosure is lacking. The artisan would be forced into burdensome experimentation so as to effectively invent what applicant only suggests may be possible.
Thus, in light of the contradictory findings in the prior art, discovery of a correlation alone is not enabling for a method of immunoassay for detecting and/or monitoring esophageal fibrosis and/or dysphagia in a patient and/or assessing the likelihood of or the severity of esophageal fibrosis and/or dysphagia in a patient and/or assessing the likelihood of or the severity of esophageal fibrosis and/or dysphagia. Only a method of performing the recited steps for detecting and/or monitoring and/or assessing the likelihood of or the severity of EoE in a patient is deemed to be enabled.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nordic (WO2016156526A1; citation 1 Under Foreign Patent Documents on the IDS dated 08/15/2023) in view of Chen et al (Trends Mol Med. 2013 Jul;19(7):410-7. doi: 10.1016/j.molmed.2013.04.001. Epub 2013 Apr 30. PMID: 23639582) and MD Anderson (https://web.archive.org/web/20201026094301/https://www.mdanderson.org/cancer-types/esophageal-cancer/esophageal-cancer-symptoms.html) as evidenced by NCBI (COL6A3, as evidenced by wayback machine at https://web.archive.org/web/20190921201710/https://www.ncbi.nlm.nih.gov/gene/1293 (available as of 09/11/2019).
Regarding claim 1, Nordic teaches a method of immunoassay for detecting in a sample a C-terminal epitope of the C5 domain of the 3 chain of collagen type VI, wherein said method comprises contacting a biofluid sample comprising said C-terminal epitope of the 3 chain of collagen type VI with an immunological binding partner which may be a monoclonal antibody, and determining the amount of binding of said immunological binding partner, wherein said C-terminal epitope is comprised in a C-terminal amino acid sequence ...KPGVISVMGT-COOH (see for example, claims 1-3 and 8-10). Nordic further teaches that the method further comprises a step of correlating the quantity of said C-terminal epitope of the 3 chain of collagen type VI determined by said method with standard normal values of said C-terminal epitope of the 3 chain of collagen type VI to evaluate a change thereof from normal levels (see for example, claim 14).
Nordic does not teach that the detected amount of binding is correlated to allow for detecting and/or monitoring esophageal fibrosis and/or dysphagia in a patient and/or assessing the likelihood of or the severity of esophageal fibrosis and/or dysphagia.
It is noted that the claim preamble fails to breathe life and meaning into the claim so as to sufficiently limit the claim. Therefore, the assay components and uses therefor of Nordic are deemed to make obvious the limitations of claim 1.
However, Chen et al teach that collagen VI is a widely distributed extracellular matrix protein highly expressed in a variety of cancers that favors tumor growth and progression, noting that COL6A3 (the Collagen Type VI Alpha 3 Chain; as evidenced by NCBI) is associated with esophageal cancer (see for example, Table 1 at page 412). Chen et al further teach that collagen VI contributes to fibrosis (see for example, column 2 of page 410, Figure 2 and its caption at page 413).
Chen et al do not explicitly teach that esophageal fibrosis or dysphagia coincide with esophageal cancer.
However, MD Anderson teaches that dysphagia is a symptom of esophageal cancer (see for example, the second bullet point) such that monitoring or detecting or assessing the likelihood of esophageal cancer would be understood to be an indirect method for monitoring or detecting or assessing the likelihood of dysphagia.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Chen et al teach that COL6A3 (collagen type VI) is strongly associated with and drives esophageal cancer which would motivate the artisan to use the methods of Nordic to assay for esophageal cancer, which the artisan would expect to correlate with incidence of dysphagia because MD Anderson teach that dysphagia is a known symptom of esophageal cancer. This meets the broadest reasonable interpretation of detecting and/or monitoring and/or assessing the likelihood of dysphagia in a patient by performing the recited steps. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 2, Nordic teaches that the immunological binding partner specifically binds to a said C-terminal epitope comprised in a C-terminal amino acid sequence of KPGVISVMGT (see for example, claims 1-2, 8-9, 17 and 19).
Regarding claim 3, Nordic teaches that the immunological binding partner does not recognize or specifically bind an elongated version of said C-terminal amino acid sequence which is KPGVISVMGTA and does not recognize or specifically bind a truncated version of said C-terminal amino acid sequence which is KPGVISVMG (see for example, claims 1-2, 4, 6).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Chen et al teach that COL6A3 (collagen type VI) is strongly associated with and drives esophageal cancer which would motivate the artisan to use the methods of Nordic to assay for esophageal cancer, which the artisan would expect to correlate with incidence of dysphagia because MD Anderson teach is a known symptom of esophageal cancer. The artisan would have found it obvious to use the immunological binding partner taught in Nordic for use in the method taught by Nordic. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 4, Nordic teaches that the biofluid may be serum, plasma, urine, or amniotic fluid (see for example, page 7 at lines 19-20; see also exemplary claim 11).
Regarding claim 5, Nordic teaches that the immunoassay may be a competition or sandwich assay (see for example, page 7 at lines 21-22; see also exemplary claim 12).
Regarding claim 6, Nordic teaches that the immunoassay may be a radioimmunoassay or an enzyme-linked immunosorbent assay (ELISA) (see for example, page 7 at lines 21-23; see also exemplary claim 13).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kubo et al (Int J Rheum Dis. 2020;23:532- 539; DOI: 10.1111/ 1756-185X.13804) is deemed relevant.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678