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 .
Status of the Claims
Claims 1, 6-8, 10-13, and 15 are pending in the application.
Claims 10-13 and 15 are withdrawn.
Claims 1 and 6-8 are the subject of this office action.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 6-8 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 diagnosis and treatment of osteoporosis, does not reasonably provide enablement for diagnosing and treating osteoporosis or osteopenia in a subject based on the claimed method steps. 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 and/or use the invention commensurate in scope with these claims.
A determination of enablement involves the consideration of the following factors: the breadth of the claims; the nature of the invention; the state of the prior art; level of one or ordinary skill; level of predictability in the art; amount of direction provided by the inventor; existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Regarding the breadth of the claims and the nature of the invention: The claims are directed to a method of diagnosing and treating osteoporosis or osteopenia.
The diagnosis is based on identification and quantification of OECs which, according to the instant specification (Pg. 8, Ln. 7-17), encompasses any cell which enhances human osteoclastogenesis and which can be characterized and identified by a number of different phenotypes and surface markers (see specification Pg. 8, Ln. 7-17; Pg. 22, Ln. 18-22; Pg. 23, Ln. 11-25; Table 1; claims 6-7).
The claims do not recite any particular step of differentiating between a diagnosis of osteoporosis and a diagnosis of osteopenia. The diagnosis step in the claim recites “diagnosing osteoporosis or osteopenia in the subject when an increase in OECs is detected as compared to a control”, thus diagnosis of either disease is based on the same observation in level of OECs.
Regarding the state of the prior art, level of predictability in the art, and the level of ordinary skill in the art: Atkins et al (RANK Expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. Journal of Bone and Mineral Research. September 2006. Vol. 21, No. 9, pages 1339-49.; IDS entered) teaches a possible correlation between OECs (CD14+RANKhigh cells) and the diagnosis and management of diseases characterized by abnormal osteoclastic activity and increased bone resorption such as osteoporosis (Abstract; Pg. 1340, Col. 1, Par. 3). Atkins demonstrates quantification of OECs in a patient sample and theorizes that such quantification may be useful in the identification and management of diseases such as osteoporosis, but Atkins does not compare quantitative levels of OECs in samples from patients with osteoporosis with levels of OECs in samples from control patients in order to actually diagnose osteoporosis based on an increase in OEC levels. Data provided by Atkins only identifies and quantifies OECs in healthy control patients (Pg. 1340, Col. 1, Par. 1).
The teachings of Atkins do not support diagnosis of osteopenia in particular, or differentiation between a diagnosis of osteoporosis and a diagnosis of osteopenia.
As such, the level of predictability in the art for one of ordinary skill in the art is low, as the prior art does not demonstrate any example of diagnosing or differentiating osteopenia from osteoporosis based only on the method steps and data gathering of the instant claim.
Regarding amount of direction provided by the inventor and the existence of working examples: The disclosure provides a number of possible variations on the phenotype of OECs which are identified and quantitated in the method of diagnosis and treatment (see specification Pg. 8, Ln. 7-17; Pg. 22, Ln. 18-22; Pg. 23, Ln. 11-25; Table 1; claims 6-7). The disclosure provides reduction to practice for the identification and quantification of OECs in PBMCs isolated from patient blood samples (Pg. 17, Ln. 19-Pg. 18, Ln. 2) wherein RANKhigh/CD66b negative cells on CD14+ cells are named as OECs. The specification indicates that there is increased cell surface expression of CCR2, C3AR1, CD51/CD61, and HLA-DR on this population of OECs in samples from 3 healthy subjects (Pg. 22, Ln. 13-17), but does not provide support which shows that these trends are also true in the OECs of patients with osteoporosis or osteopenia.
Regarding reduction to practice for a method of diagnosis and treatment, the disclosure provides only one working example/reduction to practice for the diagnosis of osteoporosis based on quantification of OECs by RANK, CD14, CD235a, and CD66b (a phenotype which notably differs from the phenotype recited in instant claims 6-7). The example shows that the percentage of OECs was increased in osteoporosis patients as compared to normal BMD subjects and osteopenia, but that there was no difference in percentage of OECs between normal BMD subjects and subjects with osteopenia. Further, the absolute number of OECs among the three groups indicates that the number of OECs is significantly higher in osteoporosis patients as compared to normal BMD subjects and subjects with osteopenia, but there was no difference between normal BMD subjects and osteopenia (Pg. 23, Ln. 11-25).
As such, the data provided in the disclosure supports diagnosis of osteoporosis based on OEC quantification (by CD14, RANK, CD235a, and CD66b) in PBMCs isolated from a patient blood sample. However, the disclosure does not support or reduce to practice diagnosis of osteopenia based on quantification of OECs. To the contrary, the example provided in the specification explicitly states that there is no significant difference in absolute number or percentage of OECs between patients with osteopenia and control subjects, such that the disclosure specifically teaches against diagnosis of osteopenia based on the claimed method steps. Additionally, neither the claims nor the specification indicates how one would differentiate a diagnosis of osteopenia from a diagnosis of osteoporosis based only on the method steps recited in the instant claims.
The specific teachings of the disclosure regarding osteopenia indicate that the method as claimed is not fully enabled even for diagnosis of osteopenia. The specification also does not provide reduction to practice for diagnosis based on different phenotypes of OECs other than the one specifically discussed in the example of Pg. 23, Ln. 11-25, which differs from the phenotypes recited in the instant claims.
Regarding the quantity of experimentation needed to make or use the invention based on the content of the disclosure: the quantity of experimentation needed to make or use the invention based on the content of the disclosure is undue. Enablement requires that the disclosure provide a reasonable level of detail which would enable one of ordinary skill in the art to understand and carry out the invention. In the instant case, such reasonable detail is lacking. There are embodiments within the scope of the instant claims which are not reasonably supported or enabled by the instant disclosure or by the prior art.
For all these reasons, and when taken together with the breadth of the claims, the specification fails to teach one of ordinary skill in the art how to make and use the claimed invention in its full scope without undue experimentation.
Claim Rejections - 35 USC § 112(b)
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 1 and 8 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 1 and 8 are rejected as indefinite because the metes and bounds of the term “osteoclast-enhancing cells (OECs)” are unclear. The specification indicates that this term is a new classification (Specification, Pg. 8, Ln. 7-10: a new circulating cell population from human blood, termed OECs. OECs enhance human osteoclastogenesis and express essential osteoclast-specific receptors such as CSF1R and RANK, but do not express CD66b, CD3, and CD19), which does not appear to be commonly recognized or used in the art. The metes and bounds of the term are unclear because it defines a particular population of cells by their function (i.e. osteoclast enhancing) but does not define the structural features that are common to the population or which are responsible for imparting that function. Additionally, the additional structural detail provided in the specification does not resolve this issue because the specification and claims identify these cells by multiple different markers and phenotypes, such that it is not clear which phenotypes, markers, or other structural features of a cell are specifically required to classify a particular cell as an OEC. For example, the specification indicates that OECs do not express CD3 and CD19, but the claims do not indicate that CD3- and/or CD19- is required in the phenotype of OECs quantified in the claimed method. The specification also indicates that OECs “express essential osteoclast-specific receptors such as CSF1R”, but CSF1R+ is not a requirement of the claimed phenotypes of OECs recited in claims 6-7.
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 1 and 6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (namely a law of nature/natural phenomenon, and abstract idea) without significantly more.
Claims 1 and 6 are directed to a method of diagnosing and treating osteoporosis or osteopenia in a subject, by quantification of circulating OECs in a sample from the subject. Wherein diagnosis is based on quantification of OECs constitutes an abstract process that may be performed in the human mind (i.e a practitioner uses OEC data to draw a conclusion about skeletal disease).
The claims are also understood to be directed to a law of nature/natural phenomenon, wherein the correlation between levels of a biomarker/cell population (OECs) and a particular disease state or risk (i.e. the naturally occurring relationship between OEC levels and osteoporosis or osteopenia) is a law of nature/natural phenomenon.
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 myeloperoxidase 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), and the natural relationship between a patient’s CYP2D6 metabolizer genotype and the risk that the patient will suffer QTc prolongation after administration of iloperidone in Vanda Pharmaceuticals Inc v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018). (See MPEP 2106.04(b)).
The correlation is naturally occurring and is a judicial exception because it exists in principle apart from any human action. The correlation itself (between OEC levels and osteoporosis or osteopenia) therefore cannot form the basis of eligibility.
As such, the diagnosis to which the claims are directed is itself a judicial exception which cannot form the basis of eligibility and cannot integrate the claims into a practical application because they are directed to performance of the judicial exception itself.
The claims further attempt to integrate the judicial exception into a practical application by integrating the judicial exceptions into a method of treatment. Regarding whether integration of the judicial exception into a method of treatment comprises integration of the judicial exception into a practical application, MPEP 2106.04(d)(2) provides the following: “One way to demonstrate such integration is when the additional elements apply or use the recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. The application or use of the judicial exception in this manner meaningfully limits the claim by going beyond generally linking the use of the judicial exception to a particular technological environment, and thus transforms a claim into patent-eligible subject matter. Such claims are eligible at Step 2A, because they are not “directed to” the recited judicial exception”. Regarding the particularity of the treatment step, the MPEP indicates that recitation of an abstract idea in conjunction with a step of, for example, “administering a suitable medication to a patient” does not integrate the judicial exception into a practical application because the treatment step is general (not particular) and is merely instruction to “apply” the judicial exception in a generic way.
As it applies to the instant case, claim 1 and its dependent claim 6 recite a treatment step at a high level of generality (“treating the subject for osteoporosis or osteopenia”) wherein this treatment step is not particular enough to integrate the judicial exceptions into a practical application because the treatment step is general and is merely an instruction to apply the judicial exception in a generic way (i.e. the treatment step generically encompasses applying any appropriate treatment for the identified disease wherein neither the disease itself nor the treatment is specifically identified).
Neither the independent claim nor the additional limitations provided in the dependent claim 6 are sufficient to either integrate the judicial exceptions into a practical application or to constitute “significantly more” than the recited judicial exceptions, because they amount to mere data gathering in support of the judicial exception (i.e. in order to diagnose the osteoporosis or osteopenia (abstract idea), one must gather data about OEC levels in a sample in order to apply the naturally occurring relationship between OEC levels and disease presence). Wherein mere data gathering in support of a judicial exception has been identified by the courts as insignificant extra solution activity which cannot constitute significantly more than the judicial exception. See MPEP 2106.05(g). Additionally, identifying and quantifying OECs is recited at a high level of generality and is not tied to any particular machine, apparatus, or specific procedure. See MPEP 2106.04(a)(2).
Furthermore, the detection of a biomarker in a biological sample has been identified by the courts to be routine and conventional activity in the life sciences arts (see MPEP 2106.05(d)(II)), and the specific measurement of OECs in a sample was known, routine, and conventional in the art before the effective filing date of the claimed invention, as demonstrated by Atkins et al (RANK Expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. Journal of Bone and Mineral Research. September 2006. Vol. 21, No. 9, pages 1339-49.; IDS entered), Ritchlin et al (US 2006/0275834 A1; IDS entered) and Lee et al (US 2014/0274953 A1) which teach identification and quantification of OECs in a sample based on detection of specific surface markers, wherein detection and quantification is carried out by routine and conventional methods in the art such as flow cytometry and FACS. As such, the art collectively indicates that identification and quantification of OECs in a sample by particular surface markers was known in the art and was routine such that it had been performed by multiple different practitioners using routine and conventional methods which were well known to one of ordinary skill in the art.
For all these reasons, the claimed elements, when taken alone or in combination, fail to include additional elements that are sufficient to either integrate the judicial exceptions into a practical application or amount to significantly more than the judicial exceptions.
Subject Matter Free of Prior Art
Claims 1 and 6-8 are rejected as described above, but appear to be free of the prior art, as best interpreted in view of the 112(b) issues presented above.
Regarding claims 1 and 6-8, Atkins et al (RANK Expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. Journal of Bone and Mineral Research. September 2006. Vol. 21, No. 9, pages 1339-49.; IDS entered), Ritchlin et al (US 2006/0275834 A1; IDS entered), and Lee et al (US 2014/0274953 A1; previously cited)
Atkins teaches identification and quantification of OECs in a sample from a subject (Abstract: human PBMNCs, BMMNCs, and GCT cells were analyzed for reactivity with anti-RANK mAbs by flow cytometry in combination with hematopoietic lineage restricted markers. GCTs were also analyzed by immunofluorescence. CD14+ monocytoid cells were sorted by FACS based on their relative RANK expression and cultured under OC-forming conditions. Importantly, sorted CD14+RANKhi PBMNCs treated with recombinant RANKL and M-CSF gave rise to approximately twice the number of osteoclasts than RANKmid or RANKlow cells; Fig. 1; Pg. 1343, Col. 2, Par. 2-Pg. 1344, Col. 1, Par. 1; Pg. 1340, Col. 2, Par. 3 and Pg. 1341, Col. 2, Par. 1: identification and quantification of OECs (CD14+RANKhi cells) by flow cytometry and FACS). Wherein cells that enhance human osteoclastogenesis and are CD14+RANKhi are understood to be OECs (see specification Pg. 8, Ln. 7-11); and
Atkins further teaches that such identification and quantification of OECs may be important for the diagnosis and management of diseases such as osteoporosis (Pg. 1340, Col. 1, Par. 3: the accurate identification of RANK-expressing pre-OCs in PB may have important clinical applications in the diagnosis and management of diseases characterized by increased bone resorption, such as osteoporosis).
Atkins differs from the instant claims in that the disclosed method only comprises identification and quantification of OECs in healthy control patients. Thus Atkins does not provide data that demonstrates that osteoporosis or osteopenia could be definitively diagnosed based on the level of OEC measured in a sample from a subject being higher than the level of OECs in a control. Atkins does not provide showing or teaching that definitively supports that OEC levels would be higher in a subject with osteoporosis or osteopenia as compared to a healthy control.
Ritchlin teaches a method comprising:
Identifying the presence of OECs in the subject and quantifying the number of circulating OECs in a sample from the subject, wherein OECs are detected by identification of cell surface markers (Par. 62: CD11b, CD14, CD51/61, and RANK are established markers of mononuclear OCP; Par. 95: obtaining a sample from the subject and assaying the number of OCPs in the sample, wherein an increase in OCP compared to a healthy control indicates an inflammatory joint disease in the subject; Par. 99: method comprises counting the number of cells comprising at least one to eight markers selected from a group comprising RANK, CD14, CD51/61). Wherein cells that enhance human osteoclastogenesis (i.e. osteoclast precursors (OCPs) in Ritchlin) and which are, for example, RANK+CD14+ are understood to be OECs (see specification Pg. 8, Ln. 7-11); and
Diagnosing a skeletal disease in the subject when an increase in OECs is detected as compared to a control (Par. 3: diagnosing and treating inflammatory joint disease; Par. 95: obtaining a sample from the subject and assaying the number of OCPs in the sample, wherein an increase in OCP compared to a healthy control indicates an inflammatory joint disease in the subject; Par. 51: condition diagnosed may be RA or PsA).
Ritchlin further teaches the method comprising treating the subject for the skeletal disease (Par. 3: diagnose and treat; Par. 48: PsA patients treated with anti-TNF agents; Par. 51).
Ritchlin differs from the instant claims in that it does not teach or suggest diagnosis or treatment of osteoporosis or osteopenia.
Regarding claim 6, Ritchlin further teaches that osteoclasts and osteoclast precursors are generally derived from populations of CD14+ monocytes (Par. 83; Par. 97: typically osteoclast precursor cell refers to a circulating monocyte/macrophage lineage cell capable of osteoblast directed differentiation into osteoclasts). Ritchlin further teaches that a panel comprising a variety of different surface expression markers can be used to identify and quantify populations of OECs (Par. 99: suitable markers with a well understood meaning in the art can include, for example, a molecule that is associated with a particular type of cell. It is also understood that markers can be assayed for their presence or absence, each of which can give information).
Regarding claim 6, Lee discloses a number of different biomarkers which can be used to classify and differentiate cell types in methods such as flow cytometry. Lee teaches specifically that CD14 is a marker that is commonly expressed on monocytes but which may also be expressed on granulocytes, and teaches that CD66b is a marker commonly expressed on granulocytes which is generally not expressed on monocytes (Par. 197; Par. 206). As such, these teachings indicate that CD66b- can be used to differentiate CD14+ monocytes and CD14+ granulocytes (wherein gating for CD66b- would exclude CD14+ granulocytes).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ritchlin to further include CD66b- in the phenotype of OECs examined, such that the OEC phenotype comprises CD14+/RANK+/CD66b-. One would be motivated to make this modification because Ritchlin teaches that the osteoclasts and osteoclast progenitors which are of interest and which are quantified in the disclosed methods are generally monocyte derived (i.e. not associated with granulocytes). Since gating for CD14+ cells may include both monocytes and granulocytes, as taught by Lee, further gating for CD66b- cells within this population would ensure that the monocytes of interest are included in the quantification of OECs, while granulocytes are excluded, thereby refining the specificity and accuracy of OEC detection. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Ritchlin teaches that the panel of biomarkers used in the method may comprise additional biomarkers (such as CD66b) which are well known in the art and which may be used to differentiate different cell types and populations.
The teachings of Ritchlin and Lee fail to meet the instant claims because they do not teach or suggest diagnosis or treatment of osteoporosis or osteopenia.
Response to Arguments
Applicant’s arguments filed 5 March 2026 have been fully considered.
Regarding the previous 112(a) rejection, applicant argues that the 112(a) rejection is overcome by the amendments to the claims which specify diagnosis and treatment of osteoporosis or osteopenia rather than a broader class of “skeletal disease”. This argument is not persuasive for the reasons discussed in the 112(a) rejection above which address these amendments to the claims.
Regarding the 112(b) rejections, Applicant argues that these are overcome by the amendments to the claims. Rejections not repeated above have been overcome by amendment and are withdrawn. However, the rejection of the term OECs in claims 1 and 8 is maintained for the reasons provided in the reference above, and Applicant has not provided any specific argument against this rejection.
Regarding the 101 rejection, Applicant argues that the 101 rejection is overcome by the amendments to the claims which incorporate the language of former claims 2-5, and which incorporate a treatment step and more particular quantification step into the independent claim. These arguments are not persuasive for the reasons provided in the 101 rejection above.
Applicant’s arguments regarding the 102 and 103 rejections are persuasive in view of the amendments to the claims and the 102 and 103 rejections are withdrawn.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLIS LUSI whose telephone number is (571)270-0694. The examiner can normally be reached M-Th 8am-6pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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