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 .
Detailed Action
Summary
This is the Final Office Action based on application 17/272012 response filed 10/10/2025.
Claims 3-11, 13-15 & 22-27 have been examined and fully considered.
Claims 1-2, 12, & 19-21 are cancelled.
Claims 16-18 are withdrawn.
Claim 22-27 were newly added.
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 3-11, 13-15 & 22-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and law of nature (natural correlation) without significantly more.
Step 1: Independent Claims 22 & 25-27 claims are directed towards methods.
Step 2A, Prong One: Claims 22 & 25-27 recite natural correlations.
The claims as amended 10/10/2025 recite, “a method of managing treatment of a disorder.” Though the claims are no longer a “screening,” claim in words and the claims do not use “diagnosis,” in the claim words, the judicial exceptions are still implicitly in the claims.
In applicant’s claims, the natural correlation is the correlation between, “a disorder that is accompanied by reduced bone density and/or calcium loss,” and the presence of alkaline earth metal portions in the blood, urine, or stool. Applicants recite a particular threshold value in the form of a calculated ratio, which marks the likelihood of the disorder. Examiner notes that this is more of a discovery of the natural correlation than a patent eligible invention. Examiner also notes that this discovery is not used in a practical application, such as administration of a particular treatment.
See example 29 of the USPTO subject matter eligibility examples.
Claims 22 & 25-27 also recite the abstract idea, “c) comparing the at least one sample value with a threshold value…” Abstract human reasoning or a generic computer is required to compare the at least one value with a threshold value.
Though a computer is not claimed in the independent claims, this would be done through a formula if on a generic computer. Formulas or equations are mathematical concepts, which are an enumerated abstract idea (MPEP § 2106.04(a)).
Step 2A, Prong Two: For Claims 22 & 25-27, these judicial exceptions are not integrated into a practical application. Upon comparison to the threshold, one of two things occurs, one of which can be, “discontinuation of treatment,” or stopping of treatment--- which means doing nothing other than making a mental decision to stop treatment. This is another abstract idea. Another treatment option is that “the patient requires no treatment,” so no treatment occurs. Another option for the treatment is, “administering,” “a therapeutic treatment that increases bone density and calcium retention.” This is not considered particular treatment, and is akin to stating, “administering a suitable treatment,” for the claimed, “disorder accompanied by bone lone and/or calcium loss.”
See MPEP 2106.04 (d)(2)(a) “This administration step is not particular, and is instead merely instructions to “apply” the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.”
Further, Claims 22 & 25-27 require:
Obtaining mass spectrometry measurements or isotope ratios or amounts of alkaline earth metal portions in the urine, blood, or stool.
The claimed the measuring seems to be just a data pull/data gathering to perform the natural correlation judicial exception. Data gathering to be used in an abstract idea (or natural correlation) is insignificant extra-solution activity, and not a particular practical application. See MPEP 2106.05(g).
Calculating;
Again- this is math and therefore an abstract idea itself
Comparing
Again, the “comparing,” is a mental process/abstract idea itself. For the comparing it is also required that this be done, “wherein the threshold value is selected independently or one or more factors determined by the patient.” Despite how the threshold is selected, it is still a threshold and part of the natural correlation itself.
Claim 25 contains an additional part to claim 22 in recitation of the threshold value of calcium to strontium of 1772 +-250 mol Ca/molSr. This is still part of the natural correlation, so does not change matters.
Claim 26 contains an additional part to claim 22 in that a simple equation is included to show how sample value and threshold value calculation is performed. This is still part of the natural correlation, and the equation itself is an abstract idea, so does not change matters.
Claim 27, specifies that no treatment is required when “osteomalacia, multiple myeloma and/or renal dysfunction is ruled out.” With respect to this, the examiner notes that “no treatment,” and “stopping of treatment,” cannot practically apply a judicial exception since nothing is done. (It is also noted that applicant doesn’t state how any of these conditions are ruled out--- but this is commented on in other rejections as well.)
Step 2B: Claims 22 & 25-27, in addition to the judicial exceptions outlined above, recite the elements “a) obtaining by mass spectrometry measurement isotope ratios or amount ratios of alkaline-earth metal portions…,” and also a treatment which can either be discontinuation of treatment, not treatment is needed or a therapeutic treatment that increases bone density and calcium retention.
Mass spectrometry measurement to gather data and treatment in this fashion are well understood, routine and conventional (WURC) in the art and therefore do not make the claims significantly more than the claimed judicial exceptions.
See MPEP 2106.05 (d) for examples that “The courts have recognized the following laboratory techniques as well understood routine and conventional.”
Nothing is dependent claims 3-11 or 13-15 change the above.
Claims 3-4 specify that the isotope ratios determined are of calcium and strontium. Again- the amount of isotopes present are part of the judicial exception itself, so this does nothing to practically apply nor add significantly more to the judicial exceptions.
Claims 5-9 specify that the measured values are compared to a threshold which was defined beforehand (sometime through a calculation, which is an abstract idea). Again- the threshold if part of the natural correlation itself, so this does nothing to practically apply nor add significantly more to the judicial exceptions. Also, for Claims 6-8, formulas or equations are mathematical concepts, which are an enumerated abstract idea (MPEP § 2106.04(a)).
Claim 10 recites the element “in step c) the difference between the two sample values is compared with a threshold value in order to additionally ascertain the kidney function.”
Claim 11 recites the element “in step c) the difference between the two sample values is compared with a threshold value in order to additionally ascertain the intestinal function.”
Claim 13 recites that the ratios are molar ratios, however measuring amounts no matter what the unit—the amounts are still part of the natural correlation judicial exception so there is nothing that practically applies nor that adds significantly more, claimed here.
Claim 14-15 recite the element “the presence of osteoporosis disease is ruled out.”
Limitations that amount to merely indicating a field of use or technological environment in which to apply a judicial exception do not amount to significantly more than the exception itself and cannot integrate a judicial exception into a practical application (see MPEP § 2106.05(h), Field of Use and Technological Environment).
Further--- the ruling out of a disease based on measured biomarkers is part of the natural correlation itself.
Further, formulas or equations are mathematical concepts, which are an enumerated abstract idea (MPEP § 2106.04(a)).
Claims 23-24 merely state that the condition or disorder that is accompanied or treated is osteoporosis. This part of the judicial exception itself and therefore does nothing to practically apply nor to add significantly more.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3-11, 13-15 & 22-27 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 22 & 25-27, contain the language, “wherein the threshold value is selected independently of one or more factors determined by the patient.” This is unclear and confusing as to what is meant. The, “factors,” as claimed are determined by the patient, so is the threshold value as well? Further—without knowing what the “factors,” are--- how is one to know if the threshold value is selected “independently,” or not.
Further in Claims 22 & 25-27, what “administering,” “ in the absence of any dietary considerations or the need to establish any sample baseline.” It is unclear here what “any dietary considerations,” are and also what a “need,” to establish a baseline is as “need is a relative term. Correction is required to clear this up.
Further for Claims 22 & 25-27--- it is unclear what “inasmuch,” “as the accompanied disorder is ruled out in the patient.” Dictionary definitions show that “inasmuch,” means “to the degree that,” or similar, however it is not clear if/ when the instant claims are “ruling out,” the disorder.
Claims 23-24, 3-11, 13-15 are rejected due to their dependency on other claims rejected under 112.
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.
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 non-obviousness.
Claims 22, 25-27, 3-7, 9, 13-15, & 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Anbar in US 20130115650 in view of Gordon in "Predicting multiple myeloma disease activity by analyzing natural calcium isotopic composition," (cited in the IDS filed 02/26/2011).
Regarding claims 22, & 25-27, Anbar discloses a method for diagnosing a disease that is accompanied by reduced bone density (“The present invention relates to the use of natural isotopes 44Ca/42Ca87Sr/86Sr as biomarkers to measure changes in bone mineral balance and loss”) (abstract). Anbar also discloses determining effective therapeutic intervention by these methods (paragraph 0005, 0007, 0015, 0028-0029, 0037, 0041-0044), the method of diagnosis and therapeutic treatment comprising the following steps:
a) determining isotope ratios or amount ratios of alkaline-earth metal portions in a sample of urine or blood or stool (“Natural calcium is a mixture of six isotopes (masses 40, 42, 43, 44, 46, and 48). The relative abundances of these isotopes are altered when calcium minerals, including bone mineral (calcium phosphate), are precipitated from aqueous solution. This alteration in isotope composition, or ‘fractionation,’ results in calcium minerals being enriched in the lighter (lower mass) calcium isotopes relative to the solution… while the solution becomes enriched in isotopically heavy calcium… This asymmetry between the isotopic effects of bone mineral formation and dissolution causes systematic and measurable changes in the calcium isotope composition of blood and urine, such that when bone mineral balance shifts so that bone formation exceeds bone dissolution (positive bone mineral balance) the Ca isotope composition of blood and urine become heavier, while when bone dissolution exceeds bone formation the isotope composition of blood and urine becomes lighter”) ([0019]),
b) thereby determining at least one sample value (“the present invention recognizes that the 44Ca/42Ca of soft tissues, and of materials like saliva, urine and hair are derived from soft tissues, are strongly affected by bone mineral balance. Measurements in these materials will provide information about bone mineral balance”) ([0020]; see [0019]),
Anbar discloses that step a) the isotope ratios or amount ratios of the alkaline-earth metal portions in the sample are determined by mass spectrometry (“multiple collector inductively coupled plasma mass spectrometry (MC-ICP-MS)”) ([0009], [0019], [0055]), and
c) comparing the at least one sample value with a threshold value, characterized in that the threshold value is selected independently of one or more factors determined by the individual patient (“Calcium isotopic compositions are expressed as 44Ca, or the difference in parts per thousand between the 44Ca/42Ca of a sample and the 44Ca/42Ca of a standard reference material [i.e., a standard reference material is independent of one or more factors determined by the individual patient]”) ([0029]).
Anbar discloses adjusting the treatment based on the results of the comparing including administering parathyroid hormone the patient which is well known and effective to induce bone formation (increase bone density) and inhibit or reduce bone loss or resorption. Anbar also teaches of maintaining the dose where efficacy is shown, but if it does not produce the desired result the therapy can be modified (increased or decreased) to produce a greater effect (paragraph 0044). Since Anbar teaches of at least one of the possible claimed treatments, it reads on the instant claim language.
Anbar discloses the method according to claim 1, wherein a disease accompanied by reduced bone density and/or calcium loss is osteoporosis, multiple myeloma ([0037]) and/or renal dysfunction (“renal osteodystrophy, renal rickets,” [0037]; “chronic renal failure,” [0038]).
Anbar does not specifically teach eliminating/ “ruling out” osteoporosis or osteomalacia (complication of multiple myeloma), multiple myeloma and/or renal dysfunction as a possibility for the disease/ruling it out, in the patient if a certain threshold value is exceeded. However, Anbar does teach that measurement of isotope ratios can be used as biomarkers to measure bone loss [0088] and to measure bone disorders such as osteoporosis, multiple myeloma (paragraph 0037) and renal diseases (paragraphs 0037-0038). Anbar also teaches that a decrease in the Ca isotope ratio can signify the onset of a negative bone mineral balance [0014]. It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention that an increase in the Ca isotope ratio can signify a positive bone mineral balance. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to provide a threshold value for the isotope ratio which would allow elimination of osteoporosis or other diseases such as osteomalacia from the diagnosis if the Ca isotope ratio was above this threshold indicating a positive or neutral bone mineral balance.
However, if this is not the case, since Anbar does not specifically call out, “threshold,” Gordon is used to remedy this.
Gordon discloses the analogous art of measuring naturally occurring calcium (Ca) isotopes to detect bone metabolism for patients with multiple myeloma (MM) (of which osteomalacia can be a complication of) (p. 2112, col. 1, para. 1). Gordon determined disease activity from peripheral blood (PB) collected from medical records (p. 2112, col. 2, para. 1) and teaches patients with active disease had statistically significant lower mean Ca isotope compositions (reported as a difference from a standard in parts per thousand (‰) δ44/42Ca) with a mean δ44/42Ca = -0.8 compared to those with non-active disease with a mean δ44/42Ca = -0.67 (p. 2114, col. 1, para. 1; see fig. 1a); low δ44/42Ca has a strong association with disease and predicts disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy and demonstrates a significant relationship between δ44/42Ca and myeloma activity likely due to increased level of bone resorption (p. 2114, col. 1, para. 3).
It is clear from Gordon’s teaching of collecting data (such as medical records) (p. 2112, col. 2, para. 1) is an experimental process that yields the optimization of a δ44/42Ca threshold that differentiates active disease or non-active disease of (p. 2114, col. 1, para. 1-3).
Therefore, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to modify the disclosure of Anbar to include wherein the threshold value in step c) for the isotope ratio 44Ca/42Ca in a blood sample according to a δ notation is δ44/42Cablood= -0.85±0.06‰ by performing routine clinical experimentation or medical record collection to optimize the threshold value of δ44/42Cablood for the benefit of differentiating active and non-active multiple myeloma as a result of bone resorption (Gordon: p. 2112, col. 2, para. 1; p. 2114, col. 1, para. 1-3; MPEP § 2144.05(II)(B)) especially given that a blood-based threshold δ44/42Ca provides the benefit of predicting disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy (Gordon: p. 2114, col. 1, para. 3).
With respect to Claim 25—please see the rejection for Claim 22 above and also the rejection for Claim 9 below as this claim encompasses the same subject matter as these two claims together.
With respect to Claim 26—please see the rejection for Claim 22 above and also the rejection for Claim 14 below as this claim encompasses the same subject matter as these two claims together.
With respect to Claim 27—the limitations are addressed along with Claim 22 above.
Regarding claim 3, Anbar discloses the method according to claim 1 wherein in step a) the isotope ratios of calcium (Ca) are determined ([0019]-[0020]).
Regarding claim 4, Anbar discloses the method according to claim 1, wherein in step a) the amount ratio of the alkaline-earth elements of calcium (Ca) to strontium (Sr) are determined (“In a second embodiment, the present invention relates to a strontium isotope tracer technique that exploits variations in 87Sr/86Sr to create and sustain an isotopic offset between dietary strontium and strontium originating in bone, which can be used to measure the rate of bone mineral loss,” [0017]; “The calcium and strontium isotope techniques give similar but not identical information… Both techniques reveal details of the speed of exchange of calcium between various soft tissue and mineralized compartments. The two techniques can be used simultaneously”) ([0033]; see [0015]).
Regarding claim 5, Anbar discloses the method according to claim 1, wherein in step c) a fixed threshold value which is independent of the individual and which was defined beforehand depending on the sample type is used as comparison value (“Calcium isotopic compositions are expressed as 44Ca, or the difference in parts per thousand between the 44Ca/42Ca of a sample and the 44Ca/42Ca of a standard reference material [i.e., a standard reference material is independent of one or more factors determined by the individual patient]”) ([0029]).
Regarding claim 6, Anbar discloses the method according to claim 1, comprising average changes in isotope ratio 44Ca/42Ca in urine samples according to a δ notation is δ44/42Ca (see figs. 4-5; [0013]-[0014], [0062]-[0063]).
However, Anbar is silent on a method wherein the threshold value in step c) for the isotope ratio 44Ca/42Ca in a blood sample according to a δ notation is δ44/42Cablood= -0.85±0.06‰ or .23±0.06‰.
Gordon discloses the analogous art of measuring naturally occurring calcium (Ca) isotopes to detect bone metabolism for patients with multiple myeloma (MM) (p. 2112, col. 1, para. 1). Gordon determined disease activity from peripheral blood (PB) collected from medical records (p. 2112, col. 2, para. 1) and teaches patients with active disease had statistically significant lower mean Ca isotope compositions (reported as a difference from a standard in parts per thousand (‰) δ44/42Ca) with a mean δ44/42Ca = -0.8 compared to those with non-active disease with a mean δ44/42Ca = -0.67 (p. 2114, col. 1, para. 1; see fig. 1a); low δ44/42Ca has a strong association with disease and predicts disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy and demonstrates a significant relationship between δ44/42Ca and myeloma activity likely due to increased level of bone resorption (p. 2114, col. 1, para. 3).
MPEP § 2144.05(II)(B) defines a result-effective variable as a variable which achieves a recognized result and which its optimal or workable ranges might be discovered through routine experimentation. Further, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. It is clear from Gordon’s teaching of collecting data (such as medical records) (p. 2112, col. 2, para. 1) is an experimental process that yields the optimization of a δ44/42Ca threshold that differentiates active disease or non-active disease of (p. 2114, col. 1, para. 1-3).
Therefore, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to modify the disclosure of Anbar to include wherein the threshold value in step c) for the isotope ratio 44Ca/42Ca in a blood sample according to a δ notation is δ44/42Cablood= -0.85±0.06‰ by performing routine clinical experimentation or medical record collection to optimize the threshold value of δ44/42Cablood for the benefit of differentiating active and non-active multiple myeloma as a result of bone resorption (Gordon: p. 2112, col. 2, para. 1; p. 2114, col. 1, para. 1-3; MPEP § 2144.05(II)(B)) especially given that a blood-based threshold δ44/42Ca provides the benefit of predicting disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy (Gordon: p. 2114, col. 1, para. 3).
Regarding claims 7 &14, Anbar discloses the method according to claim 1- see above and further comprising average changes in isotope ratio 44Ca/42Ca in urine samples according to a δ notation is δ44/42Ca (see figs. 4-5; [0013]-[0014], [0062]-[0063]).
However, Anbar is silent on a method wherein the threshold value in step c) for the isotope ratio 44Ca/42Ca in a urine sample according to a δ notation is δ44/42Caurine = 0.23±0.006‰.
Gordon discloses the analogous art of measuring naturally occurring calcium (Ca) isotopes to detect bone metabolism for patients with multiple myeloma (MM) (p. 2112, col. 1, para. 1). Gordon teaches calcium isotopic compositions in serum and urine shift to heavier Ca isotope values during bone formation and to lighter values during bone resorption (p. 2113, col. 1, para. 1). Gordon determined disease activity from peripheral blood (PB) collected from medical records (p. 2112, col. 2, para. 1) and teaches patients with active disease had statistically significant lower mean Ca isotope compositions (reported as a difference from a standard in parts per thousand (‰) δ44/42Ca) with a mean δ44/42Ca = -0.8 compared to those with non-active disease with a mean δ44/42Ca = -0.67 (p. 2114, col. 1, para. 1; see fig. 1a); low δ44/42Ca has a strong association with disease and predicts disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy and demonstrates a significant relationship between δ44/42Ca and myeloma activity likely due to increased level of bone resorption (p. 2114, col. 1, para. 3).
MPEP § 2144.05(II)(B) defines a result-effective variable as a variable which achieves a recognized result and which its optimal or workable ranges might be discovered through routine experimentation. Further, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. It is clear from Gordon’s teaching of collecting data (such as medical records) (p. 2112, col. 2, para. 1) is an experimental process that yields the optimization of a δ44/42Ca threshold that differentiates active disease or non-active disease of (p. 2114, col. 1, para. 1-3).
Therefore, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to modify the disclosure of Anbar to include wherein the threshold value in step c) for the isotope ratio 44Ca/42Ca in a urine sample according to a δ notation is δ44/42Caurine = 0.23±0.006‰ by performing routine clinical experimentation or medical record collection to optimize the threshold value of δ44/42Caurine for the benefit of differentiating active and non-active multiple myeloma as a result of bone resorption (Gordon: p. 2112, col. 2, para. 1; p. 2114, col. 1, para. 1-3; MPEP § 2144.05(II)(B)), especially given that calcium isotopic compositions in urine are known to shift to heavier Ca isotope values during bone formation and to lighter values during bone resorption (Gordon: p. 2113, col. 1, para. 1).
With respect to Claim 9 Anbar discloses the method according to claim 1, comprising average changes in isotope ratio 44Ca/42Ca in urine samples according to a δ notation is δ44/42Ca (see figs. 4-5; [0013]-[0014], [0062]-[0063])
However, Anbar is silent on a method wherein the threshold value in step c) is measure in mols and is 1772 mol Ca /mol Sr.
Gordon discloses the analogous art of measuring naturally occurring calcium (Ca) isotopes to detect bone metabolism for patients with multiple myeloma (MM) (p. 2112, col. 1, para. 1). Gordon determined disease activity from peripheral blood (PB) collected from medical records (p. 2112, col. 2, para. 1) and teaches patients with active disease had statistically significant lower mean Ca isotope compositions (reported as a difference from a standard in parts per thousand (‰) δ44/42Ca) with a mean δ44/42Ca = -0.8 compared to those with non-active disease with a mean δ44/42Ca = -0.67 (p. 2114, col. 1, para. 1; see fig. 1a); low δ44/42Ca has a strong association with disease and predicts disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy and demonstrates a significant relationship between δ44/42Ca and myeloma activity likely due to increased level of bone resorption (p. 2114, col. 1, para. 3).
MPEP § 2144.05(II)(B) defines a result-effective variable as a variable which achieves a recognized result and which its optimal or workable ranges might be discovered through routine experimentation. Further, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. It is clear from Gordon’s teaching of collecting data (such as medical records) (p. 2112, col. 2, para. 1) is an experimental process that yields the optimization of a δ44/42Ca threshold that differentiates active disease or non-active disease of (p. 2114, col. 1, para. 1-3), and this is true whether the ratio/threshold is measured in mols or by the δ notation.
Therefore, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to modify the disclosure of Anbar to include wherein the threshold value in step c) for the isotope ratio is 1772 mol Ca/Mol Sr by performing routine clinical experimentation or medical record collection to optimize the threshold value for the benefit of differentiating active and non-active multiple myeloma as a result of bone resorption (Gordon: p. 2112, col. 2, para. 1; p. 2114, col. 1, para. 1-3; MPEP § 2144.05(II)(B)) especially given that a blood-based threshold δ44/42Ca provides the benefit of predicting disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy (Gordon: p. 2114, col. 1, para. 3).
Regarding claim 13, Anbar discloses the method according to claim 1, wherein the amount ratios in step a) are determined as mass ratios of the alkaline-earth metal portions in the sample (“Calcium is a mixture of six isotopes (masses 40, 42, 43, 44,46 and 48… Changes in the Ca isotope composition are expressed as the ratio of any two calcium isotopes, with the heavier isotope in the numerator. The most commonly reported ratios are 44Ca/40Ca and 44Ca/42Ca. in [sic] most cases a rise in the value of the ratio indicates that calcium has become enriched in the heavier isotope, and a decrease that calcium has become less enriched [sic] in the lower mass isotope”) ([0019]).
Regarding claim 15, Anbar discloses the method according to claim 1, comprising average changes in isotope ratio 44Ca/42Ca in urine samples according to a δ notation is δ44/42Ca (see figs. 4-5; [0013]-[0014], [0062]-[0063]).
However, Anbar is silent on a method wherein if in step b) a sample value is determined as δ44/42Cablood and in step c) the comparison with the threshold value according to a δ44/42Cablood = -0.85±0.06‰ reveals that the sample value is greater, the presence of an osteoporosis disease can be excluded as unlikely.
Gordon discloses the analogous art of measuring naturally occurring calcium (Ca) isotopes to detect bone metabolism for patients with multiple myeloma (MM) (p. 2112, col. 1, para. 1). Gordon teaches osteoporosis is a hallmark of MM (p. 2112, col. 1 para. 1); Gordon determined disease activity from peripheral blood (PB) collected from medical records (p. 2112, col. 2, para. 1) and teaches patients with active disease had statistically significant lower mean Ca isotope compositions (reported as a difference from a standard in parts per thousand (‰) δ44/42Ca) with a mean δ44/42Ca = -0.8 compared to those with non-active disease with a mean δ44/42Ca = -0.67 (p. 2114, col. 1, para. 1; see fig. 1a); low δ44/42Ca has a strong association with disease and predicts disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy and demonstrates a significant relationship between δ44/42Ca and myeloma activity likely due to increased level of bone resorption (p. 2114, col. 1, para. 3).
MPEP § 2144.05(II)(B) defines a result-effective variable as a variable which achieves a recognized result and which its optimal or workable ranges might be discovered through routine experimentation. Further, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. It is clear from Gordon’s teaching of collecting data (such as medical records) (p. 2112, col. 2, para. 1) is an experimental process that yields the optimization of a δ44/42Ca threshold that differentiates active disease or non-active disease of (p. 2114, col. 1, para. 1-3).
Therefore, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to modify the disclosure of Anbar to include wherein the threshold for the isotope ratio 44Ca/42Ca in a blood sample according to a δ notation is δ44/42Cablood= -0.85±0.06‰ by performing routine clinical experimentation or medical record collection to optimize the threshold value of δ44/42Cablood for the benefit of differentiating active and non-active multiple myeloma as a result of bone resorption (Gordon: p. 2112, col. 2, para. 1; p. 2114, col. 1, para. 1-3; MPEP § 2144.05(II)(B)) especially given that a blood-based threshold δ44/42Ca provides the benefit of predicting disease activity independently of age, gender, hemoglobin, Ca and creatinine serum levels, current bisphosphonate and anti-myeloma therapy (Gordon: p. 2114, col. 1, para. 3).
Further, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to further modify the disclosure of Anbar to include a δ44/42Cablood > -0.85±0.06‰ reveals the presence of an osteoporosis disease can be excluded as unlikely because osteoporosis is known as a hallmark of multiple myeloma and therefore the calcium isotope ratio expressed as the delta notation would naturally correlate osteoporosis with the same threshold (Gordon: p. 2112, col. 1 para. 1).
With respect to Claim 24, Anbar teaches of the condition being osteoporosis (paragraph 0015) and of determining therapeutic intervention for osteoporosis (paragraph 0005, 0015, 0040, 0044).
With respect to Claim 23, Anbar teaches of the condition being osteoporosis (paragraph 0015) and of determining therapeutic intervention for osteoporosis (paragraph 0005, 0015, 0040, 0044).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Anbar, as applied to claim 1 above, in view of Gordon in "Predicting multiple myeloma disease activity by analyzing natural calcium isotopic composition," (cited in the IDS filed 02/26/2011), and further in view of Young in "Kinetic and equilibrium mass-dependent isotope fractionation laws in nature and their geochemical and cosmochemical significance”.
Regarding claim 8, see claim 1 rejection. Anbar and Gordon teach of the above but are silent on a method wherein the threshold value is converted to a threshold value corresponding to a different isotope ratio of calcium according to formula:
PNG
media_image1.png
141
736
media_image1.png
Greyscale
with m3 > m2 > m1, wherein m3, m2, m1 represent the mass numbers, is transferrable to other isotope ratios of calcium.
Young discloses the analogous art of fractionation laws of isotopes describing the partitioning of isotopes (abstract). Young teaches fractionation laws are characterized by the exponent ß relating the fractionation factors for two isotope ratios and that the kinetic ß is ln(M1/M2)/ln(M1/M3), wherein M1<M2<M3 and Mi and are molecular or atomic masses for transport processes (abstract). Young then teaches that fractionation curves may be written in terms of their isotope ratios (see equation (36)) or in delta notation δ (see equation (37)) (p. 1099, col. 1, para. 1-2) and can further be linearized by natural logarithm function in which ß becomes a linear variable rather than an exponential (see equation (38) (p. 1099, col. 2, para. 4-6).
Therefore, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to modify the disclosure of Anbar and Gordon to include wherein the threshold value is converted to a threshold value corresponding to a different isotope ratio of calcium according to the formula of claim 8 with m3 > m2 > m1, wherein m3, m2, m1 represent the mass numbers, is transferrable to other isotope ratios of calcium for the benefit of relating the fractionation for two isotope ratios, and therefore also the threshold value for two isotope ratios (Young: abstract; p. 1099, col. 1, para. 1-2; p. 1099, col. 2, para. 4-6).
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Anbar in view of Gordon in "Predicting multiple myeloma disease activity by analyzing natural calcium isotopic composition," (cited in the IDS filed 02/26/2011), as applied to claim 1 above, in further view of Costas-Rodriguez in "High-precision isotopic analysis of essential mineral elements in biomedicine: natural isotope ratio variations as potential diagnostic and/or prognostic markers," further in view of Heuser in "A pilot study on the user of natural calcium isotope (44Ca/40Ca) fractionation in urine as a proxy for human body calcium balance”.
Regarding claim 10, the method according to claim 1 and see Claim 1 rejection above. Anbar and Gordon do not teach what is claimed in claim 10, wherein in step b) one sample value is ascertained as δ44/42Caurine and a further sample value is ascertained as δ44/42Cablood and in step c) the difference between the two sample values is compared with a threshold value in order to additionally ascertain the kidney function.
Costas-Rodriguez discloses the analogous art of a review of high-precision isotopic analysis of essential mineral elements such as Ca to provide relevant biomedical information (abstract). Costas-Rodriguez teaches diseases that affect mineral metal metabolism affect the isotopic composition of these elements in some body “compartments” (abstract) and those changes or “fractionation” in the isotopic composition between a source compartment and a target compartment is caused by an incomplete and mass-sensitive transfer process of the isotopic element and is expressed by Δ(‰)= δtarget – δsource (p. 185, col. 1, para. 3; see equation (5) on p. 185), and that Ca isotopic analysis provides valuable information for diseases affecting bone metabolism, such as osteoporosis or multiple myeloma (MM) and that studies of Ca isotopic composition in biofluids have shown δ44Ca in peripheral blood with active MM disease were significantly lower than peripheral blood in non-active disease (p. 189, col. 2, para. 3).
Heuser discloses the analogous art of using natural calcium isotope variations in urine as a proxy for the calcium balance in the body using participants including a 4-year-old healthy boy and a 60-year-old woman known to suffer from osteoporosis (abstract). Heuser teaches disease related organ malfunction, physiological ageing processes and other diseases are known to be associated with disturbances of calcium homeostasis (p. 889, col. 2, para. 1). Heuser proposes a simple box model of the body comprising compartments (see compartments, such as gastrointestinal tract, blood, kidney, bones, urine, and soft tissue in fig. 4) and that blood plasma is the central calcium “compartment” from which Ca is exchanged with soft tissue (p. 894, col. 1, para. 1) and the isotopic difference or offset between two compartments is expressed as ∆ (p. 894, col. 1, para. 3), which allows a quantitative investigation of the influence of bone gain to bone loss by summing the ratio of calcium fluxes in and out of a compartment with the Ca isotopic compositions (expressed in delta notation δ) between compartments (p. 894, col. 1, para. 3 to col. 2, para. 1; see equations (3) and (4) on p. 894).
It is clear from the prior art that changes in isotopic compositions are calculated by the difference between a source compartment and a target compartment (Δ(‰)= δtarget – δsource) (Costas-Rodriguez: p. 185, col. 1, para. 3; see equation (5) on p. 185), and that the difference between two compartments allows a quantitative investigation of the influence of bone gain to bone loss (Heuser: p. 894, col. 1, para. 3 to col. 2, para. 1).
Therefore, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to modify the disclosure of Anbar in view of Gordon to include wherein in step b) one sample value is determined as δ44/42Castool and a further sample value is determined as δ44/42Cablood and in step c) the difference between the two sample values is compared with a threshold value in order to additionally ascertain the intestinal function for the benefit of providing valuable information for diseases affecting bone metabolism, such as osteoporosis or multiple myeloma (MM) (Costas-Rodriguez: p. 189, col. 2, para. 3) and a quantitative investigation of the influence of bone gain to bone loss as a function of isotopic difference or offset between two compartments (Heuser: p. 894, col. 1, para. 1-3 to col. 2, para. 1), and trying blood and urine as the compartments for analysis given the finite compartments identified in the art (Heuser: p. 894, col. 1, para. 1; fig. 4) specific to kidney function given that disease related organ malfunction and other diseases are known to be associated with disturbances of calcium homeostasis (Heuser: p. 889, col. 2, para. 1) see MPEP § 2143(I), KSR Rationale E “Obvious to try”).
Regarding claim 11, Anbar in view of Gordon teaches of the above, but is silent on a method wherein in step b) one sample value is determined as δ44/42Castool and a further sample value is determined as δ44/42Cablood and in step c) the difference between the two sample values is compared with a threshold value in order to additionally ascertain the intestinal function.
Costas-Rodriguez discloses the analogous art of a review of high-precision isotopic analysis of essential mineral elements such as Ca to provide relevant biomedical information (abstract). Costas-Rodriguez teaches diseases that affect mineral metal metabolism affect the isotopic composition of these elements in some body “compartments” (abstract) and those changes or “fractionation” in the isotopic composition between a source compartment and a target compartment is caused by an incomplete and mass-sensitive transfer process of the isotopic element and is expressed by Δ(‰)= δtarget – δsource (p. 185, col. 1, para. 3; see equation (5) on p. 185), and that Ca isotopic analysis provides valuable information for diseases affecting bone metabolism, such as osteoporosis or multiple myeloma (MM) and that studies of Ca isotopic composition in biofluids have shown δ44Ca in peripheral blood with active MM disease were significantly lower than peripheral blood in non-active disease (p. 189, col. 2, para. 3).
Heuser discloses the analogous art of using natural calcium isotope variations in urine as a proxy for the calcium balance in the body using participants including a 4-year-old healthy boy and a 60-year-old woman known to suffer from osteoporosis (abstract). Heuser teaches disease related organ malfunction, physiological ageing processes and other diseases are known to be associated with disturbances of calcium homeostasis (p. 889, col. 2, para. 1). Heuser proposes a simple box model of the body comprising compartments (see compartments, such as gastrointestinal tract, blood, kidney, bones, urine, and soft tissue in fig. 4) and that blood plasma is the central calcium “compartment” from which Ca is exchanged with soft tissue (p. 894, col. 1, para. 1) and the isotopic difference or offset between two compartments is expressed as ∆ (p. 894, col. 1, para. 3), which allows a quantitative investigation of the influence of bone gain to bone loss by summing the ratio of calcium fluxes in and out of a compartment with the Ca isotopic compositions (expressed in delta notation δ) between compartments (p. 894, col. 1, para. 3 to col. 2, para. 1; see equations (3) and (4) on p. 894).
It is clear from the prior art that changes in isotopic compositions are calculated by the difference between a source compartment and a target compartment (Δ(‰)= δtarget – δsource) (Costas-Rodriguez: p. 185, col. 1, para. 3; see equation (5) on p. 185), and that the difference between two compartments allows a quantitative investigation of the influence of bone gain to bone loss (Heuser: p. 894, col. 1, para. 3 to col. 2, para. 1).
Therefore, it would have been obvious to one with ordinary skill in the art before the effective filing date of the instant invention to modify the disclosure of Anbar in view of Gordon to include wherein in step b) one sample value is determined as δ44/42Castool and a further sample value is determined as δ44/42Cablood and in step c) the difference between the two sample values is compared with a threshold value in order to additionally ascertain the intestinal function for the benefit of providing valuable information for diseases affecting bone metabolism, such as osteoporosis or multiple myeloma (MM) (Costas-Rodriguez: p. 189, col. 2, para. 3) and a quantitative investigation of the influence of bone gain to bone loss as a function of isotopic difference or offset between two compartments (Heuser: p. 894, col. 1, para. 1-3 to col. 2, para. 1), and trying blood and stool as the compartments for analysis given the finite compartments identified in the art (Heuser: p. 894, col. 1, para. 1; fig. 4) specific to the intestinal function given that disease related organ malfunction and other diseases are known to be associated with disturbances of calcium homeostasis (Heuser: p. 889, col. 2, para. 1) see MPEP § 2143(I), KSR Rationale E “Obvious to try”).
Response to Arguments
Applicant's arguments filed 10/10/2025 have been fully considered but they are not persuasive.
With respect to the rejection under 35 USC 101, applicant argues that the instant re-writing of claims (cancellation of the prior pending independent claims which are re-wrote into Claims 22, & 25-27) make the claims patent eligible subject matter. The examiner disagrees. As these claims are completely new, this analysis is shown in the 101 rejection above.
All claims remain rejected under 101.
With respect to the 103 rejections, applicant argues that Anbar does not teach the comparison to a threshold and that the secondary references do not cure this deficiency. Though the examiner maintains that comparison to a threshold is routine in the art and that Anbar by itself makes this obvious, the rejection now reflects that it is Anbar in view of Gordon. Therefore, all arguments with respect to just Anbar are not commensurate in scope with the instant claims.
Applicant further argues that Anbar does not teach of the newly recited, “definitive treatment.” The examiner disagrees--- and since this subject matter is newly recited in the new Claims 25 & 25-27, it is shown in the rejection above how Anbar teaches of the claimed treatments.
Applicant further argues with respect to new Claim 22, that it is characterized “as not requiring any dietary considerations or restrictions or any need to establish sample baseline.” With respect to this--- the examiner points out that while it is “not required,” this language in the claim does not preclude the claim and the reference from teaching the subject matter which is “not required,” and the reference, Anbar in this case, teaching of this material is not a teaching away from it not being “required.”
Applicant further argues that the instant invention only requires “one single test, just one single screening of an individual patient,” and that the “single fixed threshold value for comparison to a sample value,” with respect to the instant invention is surprising. With respect to both of these points, the examiner points out, that nothing about this is claimed and therefore this argument is not commensurate in scope with the instant claims.
Applicant further emphasized the points above with respect to their “single fixed threshold value,” and argues that Anbar instead teaches determining a baseline for each individual and then a further sample must be taken and measured and that this is not a single fixed value. The examiner again notes--- that “ a single fixed threshold value,” is not claimed an instead a “threshold value is selected independently of one or more factors determined by the patient,” is claimed. Therefore, this argument is not commensurate in scope with the claims. The examiner further notes that with respect to what is actually claimed and also the “single fixed threshold value,” that applicant is arguing--- the threshold value in Anbar can read on both of these limitations since they are so broad. “A single fixed value,” does not mean that the baseline for each individual isn’t determined. Just a “single fixed value,” is “selected,” which again reads on a mental process.
Applicant further argues that the threshold value of the instant invention is “a fixed numerical value.” Again--- this is not what is claimed so is not commensurate in scope with the claims.
Applicant argues that there are advantages with respect to the instant invention and the single fixed numerical value in that it reduces costs and is simplified. With respect to this, the examiner does not agree that this is the case--- but even if it were, again what applicant is arguing is not in t