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 .
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.
Election/Restrictions
Upon further consideration, the previous requirement for restriction/election of species (Requirement mailed 10/31/2025) is withdrawn. All claims are examined. Claims 1, 8, 10, 12, 15, 16, 19, 24, 26, 29, 32, 43, 44, 50, 55, 59, 60, 65, 72, 74, 78-80, 82, 86-87, 89, 94 and 96 are pending and examined below.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/PCT/US2021/072352, filed 11/11/2021, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 63/112,820, filed 11/12/2020.
Information Disclosure Statement
The information disclosure statement filed 11/30/2023 and 12/30/2025 fail to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
The information disclosure statement filed 11/30/2023 and 12/30/2025 fail to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered.
Citations Nos. 33, 35, 36, 44, 45, 55, 83, 99, 107, 115 and 133 from IDS 11/30/2023, and citation nos. 18, 21 and 22 are lined through as either there is no copy or no concise explanation/translation of relevance.
Claim Objections
Claims 29 and 32 are objected to because of the following informalities:
Claims 29 and 32 recite the abbreviation “M-AAT”, it is suggested that anywhere Applicant recites an abbreviation, that the abbreviation be accompanied by its full meaning in order to improve clarity of the record.
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.
Claims 43, 44, 50 and 55 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 of detecting liver damage, the method comprising detecting circulating polymerized alpha-1 antitrypsin (AAT), does not reasonably provide enablement for a method of detecting an increased risk of liver damage (i.e., future damage) or an increased risk of a liver-related clinical outcome (i.e., future risk of an unspecified outcome). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
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).
Regarding the nature of the invention, the claimed invention is directed to the correlation of circulating polymeric AAT with increased risk of liver damage or increased risk of liver related clinical outcome, i.e., prediction of future risk based on the circulation of the biomarker.
Further, regarding the breadth of the claims, the claims (referring to the independent claims) broadly encompass, for example, predicting risk in any subject, inclusive of those not having liver disease/damage (i.e., any subject as the claim is not limited, and so encompasses predicting future risk in healthy subjects, future risk as in at any time in the future).
Regarding the state of the prior art, circulating polymeric AAT is recognized in the prior art as marker that correlates with liver damage/disease (disease suggesting damage). See for example, Tan et al., Circulating polymers in α1-antitrypsin deficiency, European Respiratory Journal, 43(5), (2014), p. 1501-1504, Tan et al. teach methods measuring the concentration of circulating polymerized AAT in a patient, and indicated that the circulating concentration is a result of liver damage (see Tan et al. at page 1503, para 3, Tan’s data show that circulating polymers are present in individuals with PiZZ α1-antitrypsin deficiency, that they originate from the liver; see also page 1501, end of para 2). Tan is teaching higher levels of polymer in those with abnormal liver function, liver disease and cirrhosis. Among 293 individuals, see at Figure 1, polymer concentrations demonstrate over 1 µg/mL. See for example, Figure 1 b of Tan, Tan report a patient treated with transplantation cleared polymers (see level dropping to baseline at nearly 0 mg/mL).
Tan’s results show levels dropped following transplantation (replacing the damaged/diseased liver), suggesting without damage, levels return to normal. There is nothing in the prior art to support circulating polymeric AAT as predictive biomarker of future risk of disease/damage in any subject at any time in the future of that subject. It is not readily predictable that the one of ordinary skill can readily rely on the circulating biomarker for predicting future disease.
Applicant’s working examples begin at para [0128], Example 1 refers to characterization of AAT polymer reference standards (heat treated monomer), Example 2 demonstrates detecting circulating AAT polymer in mouse model, and Example 3 detecting circulating AAT polymer in human samples. Example 4 demonstrates optimization of assay conditions, etc. However, none of the examples support the ability to rely on circulating polymeric AAT in a predictive manner for predicting risk of future damage and/or clinical outcome.
The originally filed specification provides no direction or guidance with regard to how to make or use the claimed invention in a predictive manner (relying on the marker to predict future disease/damage/outcome).
Due to the state of the prior art, which recognizes circulating polymeric AAT as correlating specifically with existing liver damage/disease, the unpredictability in the art that the marker could be used for future prediction (the lack of art correlating the marker with prediction of future outcome), and further the art supporting that in the absence of existing damage/disease, circulating levels are not present (e.g., Tan teaching a subject having had a transplant as having dropping levels), the lack of working examples using the marker a method for prediction of future risk, the breadth of the claims and the lack of direction or guidance, the specification fails to teach the skilled artisan how to make or use the claimed invention without undue experimentation.
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 43, 44, 50, 55 and 72 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 43 and 44 recite “liver-related clinical outcome”, the specification fails to describe or indicate what is meant by a “liver-related clinical outcome”. The recited language is indefinite because it is unclear what is meant by a “liver-related clinical outcome”, for example what would be considered a “liver-related clinical outcome” different from “liver damage” as is already recited at the claim.
Claim 72 recites at the preamble that the method is a method “of identifying a patient with alph-1 antitrypsin deficiency (AATD) that has an increased likelihood of responding to treatment with an AAT modulator”, thereby indicating the intended use is directed toward identification of those likely to respond. The only active step recited is “measuring the concentration of circulating polymerized alpha-1 antitrypsin (AAT) in the patient”. There is no conclusory step or active limitations recited which take the claimed measurement and amount to an identification. As presented, the claim is indefinite because it is unclear if measuring is tantamount with identification, or if additional active steps/elements are performed/required in order to achieve identification as claimed.
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 43, 44, 50, 55, 60, 65, 72, 74, 78-79, 87, 89, 94 and 96 are rejected under 35 U.S.C. 101 because the claims are directed to law of nature/natural phenomena and/or abstract ideas 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
Claim 43 recite “A method of detecting liver damage, an increased risk of liver damage, or an increased risk of liver related clinical outcome…, wherein the method comprises measuring the concentration of circulating polymerized alpha-1 antitrypsin (AAT) in the patient”.
The natural relationship to which the claims are directed (i.e., the relation between polymerized AAT and liver damage, increased risk of liver damage or an increased risk of liver related clinical outcome) is a law of nature. 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 instant claims are similar to those in Mayo as they involve a “relation itself [which] exists in principle apart from any human action” (id. at 77), namely the relationship between the naturally occurring polymerized AAT and liver damage, increased risk of liver damage or an increased risk of liver related clinical outcome.
Claim 44 recites “wherein the liver damage, the increased risk of liver damage, or the increased risk of liver-related clinical outcome is detected if: i) an elevated amount of polymerized AAT is detected as compared to a healthy patient, or ii) the measured concentration of polymerized AAT in the plasma or serum of the patient is 1µg/mL or higher”.
Claim 44 encompasses a comparison step (“an elevated amount.. compared to a healthy patient” or “is 1µg/mL or higher”). Such a step of “comparing” is also categorized as an abstract idea, namely mental processes/concepts performed in the human mind (such as a practitioner simply thinking about the measured level of polymerized AAT in relation to the level in a healthy control or a cutoff, making an evaluation, judgement or opinion). The claims, under their broadest reasonable interpretation, cover performance of identifying risk solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a control or target data represents abstract ideas.
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 (which also involved specific numerical cutoff levels).
See similarly claim 60 recites detecting AAT in the liver “if: i) an elevated amount of polymerized AAT is detected as compared to a healthy patient, or ii) the measured concentration of polymerized AAT in the plasma or serum of the patient is 1µg/mL or higher”.
As with claim 44 discussed above, claim 60 also recites abstract ideas (see as described in detail above, as the same reasoning applies presently).
Claim 72 recites “ identifying a patient with alpha-1 antitrypsin deficiency (AATD) that has an increased likelihood of responding to treatment with an AAT modulator, wherein the method comprises measuring the concentration of circulating polymerized alpha-1 antitrypsin (AAT) in the patient”.
Additionally, “identifying a patient with… (AATD) that has an increased likelihood of responding to treatment with an AAT modulator”, the method comprising only measuring polymerized AAT. The claim encompasses both a law of nature, as well as abstract ideas. Specifically, the natural relationship between naturally occurring polymerized AAT and disease status in terms of disease that is likely to respond to treatment with an AAT modulator. The claim involves a “relation itself [which] exists in principle apart from any human action” (id. at 77), namely the relationship between the naturally occurring polymerized AAT and whether a patient’s disease will response to treatment.
The claim also is categorized as an abstract idea, namely mental process/concept, as the claim amounts to observing the measured concentration of polymerized AAT and forming an observation, evaluation, judgement or opinion in one’s mind regarding the patient’s increased likelihood of responding to treatment with an AAT modulator.
Claim 79 recites “determined to have an increased likelihood of responding to treatment with an AAT modulator, if the concentration of circulating polymerized AAT is measured to be at least 1 µg/mL in plasma or serum sample”.
Claim 79 is further directed to abstract ideas as discussed in detail above (same reasoning as applied above applies presently).
Claim 87 recites “A method for measuring the efficacy of an alpha-1 antitrypsin (AAT) modulator” the method comprising “i. administering the AAT modulator to a patient with alpha-1 antitrypsin deficiency (AATD); and ii. measuring the change in the concentration of circulating polymerized AAT in the patient.”
Claim 87 is directed to abstract ideas, specifically, administering the AAT modulator and observing measured change in polymerized AAT is a mental-step type abstract (assessing efficacy).
See further claim 89, “wherein the change in the concentration of circulating polymerized AAT is determined by obtaining a first measurement of the concentration of circulating polymerized AAT shortly before administering the AAT modulator, and obtaining a second measurement of the concentration of the polymerized AAT shortly after administering the AAT modulator”.
Claim 89, determining a change is a comparison step (comparing measured value to an earlier obtained reference value), and as such is considered an abstract idea (see comparison step as discussed in detail previously above, as the same reasoning also applies presently).
Claim 94 also recites “A method for determining an efficacious dosing regimen of an ATT modulator for treating alpha-1 antitrypsin deficiency (AATD) in a patient, wherein the method comprises measuring the change in the concentration of circulating polymerized AAT in the patient”.
Similarly, “measuring the change in concentration” encompasses comparing (comparing to some reference or target data), and as discussed above, steps of comparing are considered to be abstract ideas.
Step 2A, Prong 2
Regarding claims 43 and 44, and also claims 60, 72, 79 and 94, in addition to the above discussed judicial exception(s), the claims only recite “measuring the concentration of circulating polymerized alpha-1-antitrypsin (AAT) in the patient” (or “measuring the change in concentration”, e.g., claim 94). The step of measuring concentration fails to go beyond insignificant pre-solution activity, i.e., a data gathering step necessary to use the correlation. Furthermore, the measurement step is recited at an extremely high level of generality, and is not tied, for example, to any particular machine or apparatus.
Claims 50, 65 and 74 recite limitations that further limit the subject population; however, the claim fails to recite any further steps performed as part of the claimed method. Similarly, claim 55 further limits the liver damage, thereby narrowing the judicial exception, but fails to recite additional steps/elements that amount to integration of the judicial exception into a practical application thereof.
However, the claims fail to recite any additional claimed steps/limitations which apply, rely on or use the judicial exception.
Regarding claim 78, claim 78 does recite a particular modulator (the claims directed to method of identifying a patient with alpha-1 antitrypsin deficiency (AATD) that has increased likelihood of responding to treatment with an AAT modulator, wherein the modulator is compound 1 recited at claim 78), however, this limitation merely further narrows the exception as well (for example, the claim does not require or recite a step of administering the AAT modulator, the claims are merely directed to screening likelihood of responding to the modulator as a treatment).
Regarding claim 87, the claim does recite a step of administering, namely “administering the AAT modulator to a patient with alpha-1 antitrypsin deficiency”, however, while the claim does recite administering AAT modulator, the administration step is performed in order to gather data for the mental analysis step and is a necessary precursor for all uses of the recited exception. As a result, the administration step is extra-solution activity and does not integrate the judicial exception into a practical application thereof.
Further, claim 89 recites limitations that further narrow the judicial exception(s), but fails to recite steps/elements that further apply, rely on or use the judicial exception such to integrate the judicial exception into a practical application.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Regarding the limitations recited in addition to the above indicated judicial exception(s), the claims recite steps of “measuring” concentration of polymerized AAT (or change in concentration). As indicated previously above, the additional active method step(s) directed to “measuring” is recited at a high level of generality and is not limited, for example to any specific testing technique.
Measuring polymerized AAT protein was routine and conventional in the assay art at the time. See for example each of Tan et al., Circulating polymers in α1-antitrypsin deficiency, European Respiratory Journal, 43(5), (2014), p. 1501-1504, Tan teach a method of detecting polymeric ATT in the liver of a patient with AATD, the method comprising measuring concentration of circulating polymerized ATT in the patient (see Tan et al. at page 1503, para 3, Tan’s data show that circulating polymers are present in individuals with PiZZ α1-antitrypsin deficiency, that they originate from the liver; see also page 1501, end of para 2, higher levels of polymer in those with abnormal liver function, disease, or cirrhosis).
See also Miranda et al., A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1-antitrypsin deficiency, Hepatology, 52(3), (2010), p. 1078-1088. Miranda et al. does teach in performing ELISA (see at page 1080).
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of measuring the polymerized AAT protein. See also MPEP 2106.05(g).
There is no evidence of record to indicate that the additional elements, alone or in combination, go beyond well-understood, routine and conventional activity in the art.
For all of these reasons, the claims are rejected under 35 U.S.C. 101.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 59 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tan et al., Circulating polymers in α1-antitrypsin deficiency, European Respiratory Journal, 43(5), (2014), p. 1501-1504.
Tan et al. teach a method of detecting polymeric ATT in the liver of a patient with AATD, the method comprising measuring concentration of circulating polymerized ATT in the patient (see Tan et al. at page 1503, para 3, Tan’s data show that circulating polymers are present in individuals with PiZZ α1-antitrypsin deficiency, that they originate from the liver; see also page 1501, end of para 2, higher levels of polymer in those with abnormal liver function, disease, or cirrhosis).
Claim Rejections - 35 USC § 102/ 35 U.S.C. § 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 43, 50 and 55 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Tan et al., Circulating polymers in α1-antitrypsin deficiency, European Respiratory Journal, 43(5), (2014), p. 1501-1504.
Tan et al. teach methods measuring the concentration of circulating polymerized AAT in a patient, and indicated that the circulating concentration is a result of liver damage (see Tan et al. at page 1503, para 3, Tan’s data show that circulating polymers are present in individuals with PiZZ α1-antitrypsin deficiency, that they originate from the liver; see also page 1501, end of para 2, higher levels of polymer in those with abnormal liver function, disease, or cirrhosis). The present claim language at claim 43 encompasses “detecting liver damage”, the only active step “comprises measuring the concentration of circulating polymerized…(AAT) in the patient”, Tan is performing measurement of circulating polymerized AAT in those with liver disease, and does correlate higher levels with liver damage.
Although the present claims do not recite or require limitation which amount to applying the method of detecting to those not already known to have/diagnosed with liver disease/damage, the following rejection is also made in the interest of compact prosecution.
In addition to above, Tan does also suggest additional studies to be performed in order to determine whether this biomarker is useful in predicting clinically important outcomes in those with PiZZ AAT deficiency, and does teach circulating polymers will be useful to monitor efficacy of small molecules designed to block polymerization (page 1503, last paragraph).
Based on Tan et al., it would also have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have applied the method/assay of Tan et al., detecting circulating polymerized AAT, to those patients not already known/diagnosed as having liver damage, the modification an obvious matter to try in order to indicate those subjects with liver damage, one specifically motivated to make this modification because Tan specifically suggest applying their results to assess whether this biomarker is useful for predicting clinical outcomes (Tan specifically suggests this direction). Tan specifically teach the correlation between polymerized AAT and liver disease/damage, Tan performing such assay/measurement in those subjects already diagnosed/known to have the damage. Based on Tan et al., one having ordinary skill in the art would have found it obvious to have applied Tan’s methods in a diagnostic manner to indicate damage because from Tan’s data it was known that those experiencing liver disease/damage present with circulating polymeric AAT, and because Tan specifically suggest this as a biomarker with clinical relevance (predicting outcomes and for monitoring small molecule efficacy).
One having ordinary skill in the art would have had a reasonable expectation of success because Tan already showed correlation (increasing levels) in those with damage and that circulating levels are present in all those with Z mutation AAT deficiency, that those circulating levels originate from the liver.
Regarding claim 50, Tan’s patients including patient with Z mutation in the AAT protein, those who were heterozygous for Z and another allele (see page 1503, para 2).
Regarding claim 55, Tan et al. teach liver damage that is cirrhosis, for example (see page 1501, para 1, and end of para 2,
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 8, 10, 16, 19 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al., Circulating polymers in α1-antitrypsin deficiency, European Respiratory Journal, 43(5), (2014), p. 1501-1504, in view of CD Creative Diagnostics ‘Practical Tips of ELISA’. Jun. 18, 2017. Internet Archive Wayback Machine, https://web.archive.org/web/20170618123652/https:/www.creative-diagnostics.com/Practical-Tips-of-ELISA.htm. Accessed:05/06/2026, and as evidenced by Miranda et al., A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1-antitrypsin deficiency, Hepatology, 52(3), (2010), p. 1078-1088.
Tan et al. teach (see at the abstract, also page 1501, paras 1 and 2, Figure 1) a method of measuring concentration of polymerized ATT in patient samples, the method comprising an ELISA using anti-α1-antitrypsin polymer monoclonal antibody 2C1 (see Tan refer to the ELISA reported in Miranda, Miranda describes the sandwich ELISA comprising a first and second antibody, the first antibody is rabbit polyclonal anti-α1-antitrypsin antibody, and second detection antibody was antibody 2C1 mAb, antibody 2C1 is specific for polymerized AAT and not monomeric AAT). The ELISA is measuring the amount of detection (second) antibody.
Based on the evidentiary reference, Miranda et al., Tan et al. differs from instant independent claim 1 in that it fails to teach the first antibody is the antibody that separates AAT from monomeric ATT in a patient sample.
See CD Creative Diagnostics, at 5., CD Creative Diagnostics teach in general, a monoclonal antibody is often chosen as the primary antibody to establish the highest level of specificity in an assay, and a polyclonal is chosen as secondary antibody, to amplify the signal via multiple binding events. The reference acknowledging however, that any combination can be used.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the immunoassay performed in Tan (i.e., that ELISA using 2C1 monoclonal antibody specific for polymeric form of AAT), in order to have used the 2C1 antibody as the primary antibody, and the polyclonal ATT antibody as the secondary antibody in order to achieve the highest level of assay specificity (CD Creative Diagnostics), further the modification an obvious matter to try as directed by the prior art, the prior art teaching it is known that either combination (monoclonal as primary and polyclonal as secondary, or polyclonal as secondary and monoclonal as primary) is able to be used when performing ELISA.
One having ordinary skill in the art would have a reasonable expectation of success because the prior art acknowledge either as being able to be relied upon, and further would expect success because using monoclonal as primary, based on CD Creative Diagnostics, would be expected to result in higher assay specificity (and improvement).
Regarding claim 8, Tan et al. teach plasma samples (see page 1501, paras 1 and 2, Figure 1).
Regarding claim 10, see the combination of the cited art is teaching antibody 2C1.
Regarding claim 16, see Tan as cited in detail above, Tan teach the method detection in patients with AATD (page 1501, paras 1-2, page 1503, para 3).
Regarding claim 19, Tan’s patients including patient with Z mutation in the AAT protein, those who were heterozygous for Z and another allele (see page 1503, para 2).
Regarding claim 24, Tan teach an assay that is an ELISA (cited above).
Claim(s) 12 is rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. in view of CD Creative Diagnostics, and as evidenced by Miranda, as applied to claim 1 above, and further in view of Grebe et al., WO2012/038820A2 (IDS entered 11/30/2023).
Tan et al. and the cited prior art teach a method substantially as claimed, however, Tan et al. and the cited art as combined above, teach as the first antibody, antibody 2C1 specific for polymerized AAT and not monomeric AAT (see as cited in detail previously above).
Tan et al. and the cited art differs from the claimed invention in that it fails to teach first antibody is selected from antibody LG96 or MG97 (claim 12).
Grebe et al. teach immunoassay for the detection of Z-AAT (protein present in a sample from a PiZ gene carrier, i.e., referring to the Z allele mutation discussed previously above (see referring to Tan). Grebe et al. teach Z-AAT protein refers to Z-AAT polymers (page 6). Grebe teach capturing Z-AAT protein using an immobilized capture antibody where the antibody is LG96 (see page 2 and page 4, description of figure 1). See also at page 3, description of Figure 2, the antibody binds polymeric (Z) form but not monomeric form of the protein (M-form).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Tan et al. and the cited prior art in order to rely on LG96 monoclonal antibody in place of 2C1 monoclonal antibody as a simple substitution of one art recognized, available antibody for binding polymeric ATT for another, both known in the art and both recognized as binding polymeric form of the protein and not the monomer. Given that both were known for the same purpose, one having ordinary skill in the art would have a reasonable expectation of success using one in place of the other.
Claim(s) 15 is rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. in view of CD Creative Diagnostics, and as evidenced by Miranda, as applied to claim 1 above, and further in view of Mancio-Silva et al., Improving Drug Discovery by Nucleic Acid Delivery in Engineered Human Microlivers, Cell Metabolism, 29, (2019), p. 727-735.
Tan et al. and the cited art teach a method substantially as claimed, the ELISA comprising a rabbit polyclonal anti-AAT antibody, however, fail to teach the second (polyclonal antibody) is antibody A80-122P
However, see for example, polyclonal anti-AAT were known and available to those of ordinary skill in the art at the time. Mancio-Silva for example teach at page 736 a list of antibodies by commercial source and catalog number. Goat anti-human alpha1-antitrypsin antibody was known and available at the time by Bethyl by catalog number A80-122P (AB_2285693).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Tan et al. and the cited art in order to use polyclonal antibody A80-122P in place of the polyclonal antibody taught by Tan (as evidenced by Miranda) as a simple substitution of one art recognized, commercial antibody known for binding AAT for another, both antibodies were commercially available and known for the same purpose. There does not appear to be any art recognized advantage in using one of the other. One having ordinary skill in the art would have had a reasonable expectation of success making them modification because both are polyclonal antibodies used for immunoassay binding to AAT.
Claim(s) 24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. in view of CD Creative, and as evidenced by Miranda et al., as applied to claim 1 above, and further in view of Qin et al., US Patent No. 10,024,861 B2.
Regarding claims 24 and 26, as cited above Tan et al. teach ELISA, however, fails to teach a chemiluminescent immunoassay, for example an electrochemiluminescent immunoassay (claims 24 and 26).
Qin et al. teach chemiluminescent immunoassay as being advantageous in that it’s highly sensitive, has a broad linear range, rapid analysis speed, simple operation, and ready for automation (col. 1, lines 21-25). Qin et al. teach labels for such as able to bind antibody or antigen molecule to produce labeled antibody/antigen (col. 1, 51-55). See at col. 11, lines 24-27, teach the detection scope of the electrochemiluminescence immunoassay as wider than that of an ELISA.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date to have modified the method of Tan and the cited art in order to perform the assay as a electrochemiluminescent immunoassay instead of an ELISA, as a simple substitution of one known immunoassay format for another, both used for detecting an antigen in sample, one motivated to make the modification because of the advantages afforded to electrochemiluminescent assay (regarding sensitivity, broad linear range, analysis speed, simplicity of operation, etc.) and because of the wider detection scope as compared to detection using ELISA (Qin). One having ordinary skill in the art would have a reasonable expectation of success because like ELISA as in Tan, Qin demonstrates electrochemiluminescent assay capable of sandwich assay format (Figure 1), and that the label can be used to label an antibody (capable of being used as a labeled antibody conjugate).
Claim(s) 29 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. in view of CD Creative Diagnostics, as evidenced by Miranda et al., as applied to claim 24 above, and further in view of Miranda et al. and Ferrarotti et al., How can we improve the detection of alpha1-antitrypsin deficiency, PLOS One, 10(8), (2015), p. 1-12.
Tan et al. and the cited prior art teach a method substantially as claimed (see above, regarding claim 24). Tan et al. is teaching the ELISA performed according to Miranda et al. (see Miranda et al. previously cited as an evidentiary reference), however Tan et al. fails to teach the calibration/standards produced by heat treating the monomeric form of AAT for 4-18 hours.
Miranda et al. does teach in performing ELISA, providing standards (M and Z α1-antitrypsin).
Miranda et al. does also teach producing polymeric form by heat induced polymerization of ATT (see page 1080, col. 2, para 1, heating at 60°C for 1 hour), however, Miranda et al.’s methods differ in that they are not heat treating for 4-18 hours.
However, see also Ferrarotti et al. who teach a molecular profile of heat-treated purified A1AT (see at Figure 3). Ferrarotti investigated heat treatment to induce polymerization at 60°C over time, Ferrarotti found that heating for A1AT for 45 min or longer resulted in remarkable decrease in signal from the native protein (see caption, and page 7, heating to 120 minutes leads to the formation of increasing amounts, and prolonged heating up to 240 minutes had no additive effect on A1AT polymerization.
Tan et al. and the cited prior art is teaching methods of measuring the concentration of polymerized AAT, and although Tan et al. is silent as to the standards/calibrations, it would have been prima facie obvious to one having ordinary skill in the art performing quantitative ELISA to have provided standards (calibration controls) for quantitative detection, as in Miranda et al., as an obvious matter of applying a known technique to a known method (see Miranda et al. is teaching details of the ELISA assay as performed in Tan, and does teach the use of standards (standard samples for calibration). One having ordinary skill in the art performing the ELISA as in Tan would have applied the technique as in Miranda in order to determine concentration from detected signal, and the results would have been predictable because Tan is performing ELISA as in Miranda (and as such, one would have had a reasonable expectation of success).
Regarding the standards/calibration controls, it would have been further obvious to have modified the standards to have produced polymeric form (the targeted analyte) by heat treatment of the monomer (as in Miranda et al. or Ferrarotti), namely by heating the monomer at 60°C to cause polymerization as an obvious of matter of applying a known technique for producing standard that is consistent with targeted analyte, specifically heat treatment is a known technique recognized in the prior art for producing polymeric form of AAT. One having ordinary skill in the art would have had a reasonable expectation of success using a known technique in the art for producing polymeric form of the protein, with a predictable expectation of success since both Miranda and Ferrarotti recognized heat treatment as causing polymerization (expect success using a known technique for its intended purpose).
Even further, it would have been prima facie obvious to one having ordinary skill to have arrived at any time in a duration as claimed, namely 4-18 hours, as an obvious matter of routine optimization of experimental conditions. In particular, the prior art taught heat treatment as a recognized technique to cause polymerization of AAT, further the art recognized that from 120 minutes to more than 120 minutes (for example, up to 240 minutes), polymerization remained unchanged (see Ferrarotti teaching beyond 120 minutes no additive polymerization occurred, any time 120 minutes and beyond based on the art is expected to predictably behave the same, i.e., achieve the same result). It would have been obvious to have optimized conditions to achieve maximum polymerization, thereby arriving at a duration of at least 4 hours, because based on Ferrarotti, at 240 minutes one having ordinary skill would expect to achieve maximum polymerization (this duration ensuring complete polymerization). In particular, any duration after 120, based on the cited art, would be considered suitable for achieving polymerization because the prior art supports that 120 or more would be an incubation achieving the same result.
Regarding claim 32, the combination of the cited art teach heating at 60°C.
Claim(s) 44, 60 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. (as applied to claim 43 or claim 59 above) and further in view of Buechler et al., US PG Pub No. 2004/0121343.
Tan et al. and the cited prior art teach a method substantially as claimed (see as cited in detail above). Tan et al. is teaching mean circulating levels as 36.3 +/-33.3 in those with PiZZ alpha-1 antitrypsin deficiency, Tan is teaching higher levels of polymer in those with abnormal liver function, liver disease and cirrhosis. Among 293 individuals, see at Figure 1, polymer concentrations demonstrate over 1 µg/mL. See for example, Figure 1 b of Tan, Tan report a patient treated with transplantation cleared polymers (see level dropping to baseline at nearly 0 mg/mL).
However, although the Tan and the cited art is as set forth in detail above (see referring to the analysis at claim 43), Tan et al. and the cited art fail to teach wherein liver damage is detected if i) an elevated amount of polymerized AAT is detected as compared to healthy patient, or ii) the measured concentration of polymerized AAT in the plasma or serum of the patient is 1 µg/mL or higher.
Buechler et al. 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 (healthy) 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.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date to have modified the method as taught by Tan et al. and the cited prior art in order to indicate disease by either observing an elevated amount relative to ana mount compared to a healthy subject, or based on a level that is above 1 µg/mL or higher because it was well understood in the prior art before the claimed invention to compare a clinical marker to an value considered “normal” to indicate the presence or absence of disease. This is a modification considered to be an obvious matter of applying a known technique to a known method, see specifically Buechler, a clinical marker can be compared to a “normal” value in order to indicate presence of a disease. In the present case, Tan et al. and the cited art support the correlation of elevated polymeric AAT with liver disease/damage. As a result, one having ordinary skill would have a reasonable expectation of success indicating damage based on a measured elevated amount relative to those considered to be “normal” (i.e., healthy).
Additionally, regarding a threshold amount, it would have been further prima facie obvious to have selected µg/mL or higher as indicative of damage because Tan et al. teach higher levels as correlating with disease/damage, Tan specifically showing those known to have disease above 1 µg/mL (referring to Figure 1) (whereas a subject having been treated with transplant, non-damaged liver, had clearance of polymeric forms in circulation (see also referring to Figure 1). Additionally, it would have been obvious to have arrived at 1 µg/mL as threshold/cutoff level, in light of Tan’s data, because a selected cutoff (threshold) is a value selected in in order to distinguish between a positive and negative results and the selected value effects the number of false negatives and positives (i.e., trades off between sensitivity and specificity, see Buechler teaching one can adjust the diagnostic threshold in order to optimize clinical sensitivity and specificity). It would have been obvious to have arrived at the claimed value, namely 1 µg/mL, through routine optimization, a practitioner selecting a value that distinguishes between normal and diseased/damaged liver based on levels known to correlate with damage in the prior art, one having ordinary skill selecting the value through routine optimization to achieve a desired sensitivity/specificity.
One having ordinary skill in the art would have a reasonable expectation of success because Buechler supports this as a value to be selected, namely through optimization to achieve a desired result (desired between sensitivity and specificity, i.e., the value is a result effective variable).
Regarding claim 60, see as cited above, the prior art teaching a method of detecting polymeric ATT in the liver (correlating with disease/damage). It would have been obvious to have indicated polymeric ATT upon detection of a concentration elevated as compared to a healthy control subject, or at 1 µg/mL or above, for the same reasons as applied above (see the reasoning as applied to claim 44, as the same reasoning also applies presently).
Regarding claim 65, claim 65 depends from claim 60, see Tan’s patients including patient with Z mutation in the AAT protein, those who were heterozygous for Z and another allele (see page 1503, para 2).
Claim(s) 72 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al.
Claim 72 is recited as a method “of identifying a patient with alpha-1 antitrypsin deficiency (AATD) that has an increased likelihood of responding to treatment with an AAT modulator”, the method recites as the only active method step “measuring the concentration of circulating polymerized alpha-1 antitrypsin (AAT) in a patient”. The claim does not recite any further steps/actions which amount to performing an action of identifying, the claim, as presented reads as though measuring a concentration as claimed is tantamount with identifying increased likelihood, i.e., that it naturally follows that measuring concentration as claimed, results in identification.
As cited previously above, Tan et al. teach a method detecting in subjects with AATD, polymeric AAT, Tan teaching circulating polymers are present in all individuals with PiZZ AATD originating from the liver (see as cited in detail previously above, and at page 1503, para 3). Tan et al. teach (para 3) this marker (circulating polymeric AAT) as useful in monitoring efficacy of small molecules designed to block polymerization.
Tan et al. does teach measuring as claimed, and from the teaching of Tan et al. it is understood that those with AATD are subjects with increased likelihood of treatment with AAT modulating therapeutics (i.e., it would naturally follow that those with AATD have an increased likelihood of responding to an AATD treatment, e.g., as compared to those that do not have AATD).
Nonetheless, although the present claims are not limited to those not previously indicated to have AATD, or further does not recite any limitations specifically directed to an action of identification, it would also be obvious to have applied the measurement assay (the measurement of polymeric AAT concentration of Tan) for the purpose of identifying those with AATD, i.e., those who would likely respond to treatment with a modulator), because Tan specifically suggest the measurement as useful in monitoring efficacy of small molecules specifically designed to block polymerization (i.e., modulators). One having ordinary skill would have a reasonable expectation of success because Tan specifically suggest the marker measured for this purpose.
Regarding claim 74, Tan’s patients including patient with Z mutation in the AAT protein, those who were heterozygous for Z and another allele (see page 1503, para 2).
Claim(s) 79, 80 and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al., as applied to claim 72 above, and further in view of Buechler et al.
Regarding Tan et al., Tan et al. teach a method substantially as claimed (referring to claim 72 above), however, fails to teach determined to have an increased likelihood if the concentration of circulating polymerized AAT is measured to be at least 1 µg/mL
Buechler et al. 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 (healthy) 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.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date to have modified the method as taught by Tan et al. and the cited prior art in order to indicate disease (AATD) by either observing an elevated amount relative to ana mount compared to a healthy subject, or based on a level that is above 1 µg/mL or higher because it was well understood in the prior art before the claimed invention to compare a clinical marker to an value considered “normal” to indicate the presence or absence of disease. This is a modification considered to be an obvious matter of applying a known technique to a known method, see specifically Buechler, a clinical marker can be compared to a “normal” value in order to indicate presence of a disease.
In the present case, Tan et al. and the cited art support the correlation of elevated polymeric AAT with AATD (and liver disease/damage). As a result, one having ordinary skill would have a reasonable expectation of success indicating damage based on a measured elevated amount relative to those considered to be “normal” (i.e., healthy).
Additionally, regarding a threshold amount, it would have been further prima facie obvious to have selected µg/mL or higher as indicative of damage because Tan et al. teach higher levels as correlating with disease/damage, Tan specifically showing those known to have disease above 1 µg/mL (referring to Figure 1) (whereas a subject having been treated with transplant, non-damaged liver, had clearance of polymeric forms in circulation (see also referring to Figure 1). Additionally, it would have been obvious to have arrived at 1 µg/mL as threshold/cutoff level, in light of Tan’s data, because a selected cutoff (threshold) is a value selected in in order to distinguish between a positive and negative results and the selected value effects the number of false negatives and positives (i.e., trades off between sensitivity and specificity, see Buechler teaching one can adjust the diagnostic threshold in order to optimize clinical sensitivity and specificity). It would have been obvious to have arrived at the claimed value, namely 1 µg/mL, through routine optimization, a practitioner selecting a value that distinguishes between normal and diseased (AATD)/damaged liver based on levels known to correlate with damage in the prior art, one having ordinary skill selecting the value through routine optimization to achieve a desired sensitivity/specificity.
One having ordinary skill in the art would have a reasonable expectation of success because Buechler supports this as a value (cutoff) to be selected, namely through optimization to achieve a desired result (desired between sensitivity and specificity, i.e., the value is a result effective variable).
Regarding claim 80, in addition to that cited and discussed in detail above, it would have been further obvious, upon measuring and identifying those with likelihood of responding to treatment (i.e., those with disease), to subsequently treat those above the threshold level with a modulator (a small molecule targeted polymerization, as suggested by Tan et al.), to mitigate the disease (one motivated because Tan specifically suggest using circulating polymer to monitor efficacy, as such it would be obvious to follow Tan’s suggestion). One having ordinary skill in the art would have a reasonable expectation of success because Tan specifically suggests treatments to modulate polymerization, and it would be expected that those with AATD (those with polymerized AAT) would benefit from administration of such molecules (i.e., are those in need of treatments for this particular diagnosis).
Regarding claim 82, Tan’s patients including patient with Z mutation in the AAT protein, those who were heterozygous for Z and another allele (see page 1503, para 2).
Claim(s) 87, 89, 94 and 96 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. in view of Demartino et al., WO03/061659A1.
Tan et al. is as cited in detail previously above, Tan specifically suggest using polymeric AAT as a biomarker for this purpose (Tan teach polymeric AAT correlated with those with AATD, and liver damage/disease, the art specifically suggested polymeric AAT to monitor small molecule efficacy, i.e., for those designed to block polymerization as noted by Tan, recited as a treatment for those with AATD).
It would have been prima facie obvious to one having ordinary skill in the art to have modified Tan et al. in order to further screen efficacy of a modulator as referenced by Tan (small molecule that targets polymerization), one motivated to measure efficacy because Tan specifically suggest using polymeric AAT as a biomarker for this purpose (Tan teach polymeric AAT correlated with those with AATD, and liver damage/disease, the art specifically suggested polymeric AAT to monitor small molecule efficacy, i.e., for those designed to block polymerization as noted by Tan, recited as a treatment for those with AATD).
Further it would have been obvious, when screening efficacy, to have applied the method of Demartino et al., namely, to administer the modulator and measure the change in the correlating biomarker (in the case of AATD, polymeric AAT) as an obvious matter of applying a known technique, specifically because the technique of Demartino is demonstrated as for the purpose of screening modulator efficacy (monitoring change in the targeted biomarker). One having ordinary skill would have a reasonable expectation of success because Tan teach small molecules that block polymerization (i.e., modulator) as a therapeutic for AATD, and one having ordinary skill in the art would have a reasonable expectation of success using a known technique for its intended purpose (the known technique of Demartino for screening modulator efficacy).
Regarding claim 94, the claim recites “method for determining an efficacious dosing regimen of an AAT modulator for treating…AATD”, the method comprising only a step of “measuring the change in concentration”. Tan et al., as discussed in detail above specifically suggests measuring polymerized circulating AAT for the purpose of screening small molecule drug efficacy discussed in detail above). As a result, although Tan et al. did not perform methods of determining efficacious dosing regimen, Tan did perform the same measurement (as the only active method step claimed), and based on Tan described above, it would be obvious to apply that measurement (the monitoring of polymerized AAT) for the purpose of determining efficacious dosing because Tan specifically suggest this measurement for that particular purpose (for efficacy).
However, Tan fails to explicitly teach measuring a change in concentration (although suggested for efficacy, Tan did not perform such measurement monitoring change as a result of a modulator).
Regarding efficacy, methods for monitoring efficacy of a therapeutic comprise administering the amount of the modulator, measuring change in the level toward a normal level to determine the efficacy of the modulator (see e.g., page 42, lines 7-15, and claim 47 of Demartino et al.).
It would have been prima facie obvious to one having ordinary skill in the art when relying on the biomarker to screen for efficacy to monitor change in the marker, namely, to administer the modulator and measure the change in the correlating biomarker (in the case of AATD, polymeric AAT), as in Demartino et al., as an obvious matter of applying a known technique for monitoring efficacy, specifically because the technique of Demartino is demonstrated as intended for the purpose of screening modulator efficacy (monitoring change in the targeted biomarker). One having ordinary skill in the art would have a reasonable expectation of success using a known technique for its intended purpose (the known technique of Demartino for screening modulator efficacy).
Regarding claim 96, the combination of the cited art addresses measuring a level, administering a modulator, monitoring change (change in level as a result of the administration).
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 72, 74 and 78-79 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,884,672B2 in view of Tan et al.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
‘672 recites modulators of AAT which encompass the modulator recited at claim 78 of the present application, see at ‘672, claims 1-3, the compound comprising the formula:
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100
194
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,
R0 selected from those shown at col. 831, including:
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106
82
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R1 selected from those at col. 831-832, including:
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48
76
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R2 selected from those at col. 830, including
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86
130
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.
‘672 also teach their compound as part of a pharmaceutical composition for treating AATD (see at claims 7-11 of the copending application).
The copending application fails to recite a method of identifying patients with AATD that have an increased likelihood of responding to treatment with an AAT modulator, however because ‘672 specifically disclose their modulator composition as a suitable treatment for those with AATD, it would be expected that those patients with AATD be identified as having an increased likelihood.
However, ‘672 fails to recite the method for identification as a method that comprises “measuring the concentration of circulating polymerized AAT in a patient.
See however, Tan et al. teach measuring circulating polymeric AAT in patients, and Tan et al. correlate circulating polymers with those with PiZZ alpha1-antitrypsin deficiency (see cited in more detail previously above, referring to page 1503, para 3 of Tan et al., Tan suggesting this biomarker as clinically relevant for applications such as monitoring small molecule efficacy designed to block polymerization).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified ‘672 in order to measure circulating polymeric AAT in order to indicate those with AATD, as in Tan et al., and to further conclude that those subject’s would have an increased likelihood of responding to a modulator, such as the composition of ‘672 because Tan specifically indicate a correlation between the circulating polymer and AATD, Tan suggesting this biomarker as clinically relevant for applications such as monitoring small molecule efficacy designed to block polymerization. Further one would have found it obvious that those with AATD have an increased likelihood responding to treatment with a modulator as that of ‘672 because ‘672 explicitly discloses this compound for treating AATD (as such one would expect success screening for AATD to see who would likely respond to treatment with the AATD therapeutic).
Regarding claim 74, Tan’s patients including patient with Z mutation in the AAT protein, those who were heterozygous for Z and another allele (see page 1503, para 2).
Regarding claim 78, see as cited in detail above (regarding claim 72), the copending application teach a compound including that presently claimed.
Claims 87, 89, 94 and 96 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,884,672 in view of Tan et al., and Demartino et al., WO03/061659A1.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
’672 recites a composition comprising a compound that is an AAT modulator (see as cited in detail previously above), ‘672 recites this composition as a therapeutic for those with ATTD.
However, ‘672 fails to recite a method for measuring efficacy of an AAT modulator, the method comprising administering the modulator to a subject with AATD, measuring a change in the concentration of circulating polymeric AAT (claims 87 and 89).
Tan et al. is as cited in detail above, Tan et al. teaching measuring circulating polymeric AAT in patients, and Tan et al. correlate circulating polymers with those with PiZZ alpha1-antitrypsin deficiency (see cited in more detail previously above, referring to page 1503, para 3 of Tan et al., Tan specifically suggesting this biomarker as clinically relevant for applications such as monitoring small molecule efficacy designed to block polymerization).
Regarding efficacy, methods for monitoring efficacy of a therapeutic comprise administering the amount of the modulator, measuring change in the level toward a normal level to determine the efficacy of the modulator (see e.g., page 42, lines 7-15, and claim 47 of Demartino et al.).
It would have been prima facie obvious to one having ordinary skill in the art to have modified ‘672 to further screen efficacy of the modulator of ‘672, one motivated to measure efficacy because Tan specifically suggest using polymeric AAT as a biomarker for this purpose (Tan teach polymeric AAT correlated with those with AATD, and liver damage/disease, the art specifically suggested polymeric AAT to monitor small molecule efficacy, for molecules such as that of ‘672, recited as a treatment for those with AATD).
Further it would have been obvious, when screening efficacy, to have applied the method of Demartino et al., namely, to administer the modulator and measure the change in the correlating biomarker (in the case of AATD, polymeric AAT) as an obvious matter of applying a known technique, specifically because the technique of Demartino is demonstrated as for the purpose of screening modulator efficacy (monitoring change in the targeted biomarker). One having ordinary skill would have a reasonable expectation of success because ‘672 teach their modulator as a therapeutic for AATD, and one having ordinary skill in the art would have a reasonable expectation of success using a known technique for its intended purpose (the known technique of Demartino for screening modulator efficacy).
Regarding claim 94, see the combination of ‘672, Tan et al. and Demartino et al., the combination addressed determining efficacious dosing regimen, the method comprising measuring circulating polymerized AAT.
Regarding claim 96, the combination of the cited art addresses measuring a level, administering a modulator, monitoring change (change in level as a result of the administration).
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
