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 .
Status of Application, Amendments and/or Claims
The amendment, filed 07 April 2023, has been entered in full. Claims 1-20 are canceled. New claims 21-36 are added.
Applicant’s election without traverse of Group I (claims 21-33) in the reply filed on 07 April 2026 is acknowledged Claims 34-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07 April 2026. Claims 21-33 are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 07 April 2023) was received and complies with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. It has been placed in the application file and the information referred to therein has been considered as to the merits.
Claim Objections
Claim 25 is objected to because of the following informalities:
The word “at” should be inserted after the phrase “is administered” (see claim 25, line 2). Appropriate correction is required.
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 31-33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions (an abstract idea and a law of nature) without significantly more.
Claim 31 is directed to a method of treating alopecia areata in a subject that improves severity of hair loss in the subject, the method comprising:(a) selecting a subject having or suspecting of having alopecia areata; (b) measuring total IgE serum in the subject, wherein IgE is a biomarker of alopecia areata; (c) administering an initial dose of a pharmaceutical composition comprising dupilumab; wherein the initial dose of the pharmaceutical composition is administered if the total IgE serum in the subject is elevated compared to a subject not having or not suspecting of having alopecia areata.
STEP 1: Are the claims directed to a process, machine, manufacture or composition of matter? YES. The instant claims are directed to a process.
STEP 2A (The Judicial Exception) PRONG ONE: Do the claims recite a law of nature, a natural phenomenon (i.e. product of nature) or an abstract ideal? Yes, the instant claims are directed to an abstract ideal and a law of nature.
The instant claims are directed to an abstract ideal for the following reasons:
The claim recites the step “selecting a subject having or suspected of having alopecia areata”.
The claim also recites the step "wherein the initial dose of the pharmaceutical composition is administered if the total IgE serum in the subject is elevated compared to a subject not having or not suspecting of having alopecia areata”.
The “selecting” and "comparing" steps can be performed using mental steps or basic thinking, representing an abstract idea.
Limitations such as selecting, comparing, assessing or determining, which under its broadest reasonable interpretation, covers performance of the limitation in the mind. The claim falls within the “Mental Processes” as it involves evaluating and judging. Accordingly, the claim recites an abstract ideal (see Univ. of Utah Research Found V. Ambry Genetics Corp., 113 USPQ2d 1241 (Fed. Cir. 2014)).
The instant claims are directed to a law of nature for the following reasons:
The claims recite a naturally occurring correlation between the amount of total IgE serum in a sample and the diagnosis of alopecia areata in a subject. The relationship itself is a natural consequence of a substance that the body produces when a particular condition/disease is present.
Accordingly, the claims recite a Law of Nature similar to the naturally occurring correlation found to be law of nature by the Supreme Court in Mayo Collaborative Services V. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012) (see also, Cleveland Clinic Foundation V. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017);; Ariosa Diagnostics, Inc. V. Sequenom, 788 F.3d 1371,
1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015)).
STEP 2A PRONG TWO: Do the claims recite additional elements that integrate the exception into a practical application of the exception? NO.
It is noted that claims 31, 32 and 33 recite a specific administered treatment.
However, claim 31 also recites the limitation “..administering an initial dose of a pharmaceutical composition comprising dupilumab; wherein the initial dose of the pharmaceutical composition is administered if the total IgE serum in the subject is elevated compared to a subject not having or not suspecting of having alopecia areata.
The administration step recited in claim 31 is in an alternative format; it is a conditional step. The subject may or may not be selected for treatment, depending upon the total IgE serum level. For instance, the subject is not selected and administered dupilumab if the sample from the subject does not have elevated total IgE serum levels compared to a control.
STEP 2B: Does the claim provide an inventive concept, i.e. does the claim recite additional element(s) or a combination of additional elements that amount to significantly more than the judicial exception in the claim? NO.
The method of measuring total IgE serum in samples obtained from subjects is routine and well-established. For example, the state of the art at the time of filing the instant application teaches obtaining samples from subjects having or suspected of having alopecia areata and measuring serum IgE levels by employing an enzyme‑linked immunosorbent assay. Bakry et al. teach taking blood samples from subjects having or suspected of having alopecia areata. Bakry et al. teach that subjects with other conditions that might elevate serum IgE were excluded from the study. Bakry et al. teach age- and sex-matched healthy subjects were selected as a control group (Bakry et al. Total serum immunoglobulin E in patients with alopecia areata. Indian Dermatology Online Journal -Volume 5 - Issue 2; April-June 2014). There is no meaningful limitation in this step that distinguishes it from well-understood, routine and conventional data gathering activity engaged in by scientists prior to Applicant's invention at the time of filing.
Therefore, the instant claims as a whole do not amount to significantly more than the exceptions themselves and do not qualify as eligible subject matter under 35 U.S.C. §101. See also Diamond V. Chakrabarty, 447 U.S. 303 (1980) and Association for Molecular Pathology V. Myriad Genetics, 569 U.S. 133 S. Ct. 2107, 2116, 106 USPQ2d 1972 (2013) and www.uspto.gov/patcnt/laws-and-regulations/cxamination-policy/subjcct-mater-cligibility
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 21-33 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 improving severity of hair loss in a subject, the method comprising administering to a subject in need thereof an effective amount of dupilumab, wherein the subject has or is suspected of having alopecia areata”
“..wherein dupilumab is administered at a single initial dose comprising 100 mg to 600 mg dupilumab”.
“..wherein the subject is a human adult patient having alopecia areata and dupilumab is administered at a single initial dose comprising 600 mg dupilumab; or the subject is a human child patient having alopecia areata and dupilumab is administered at a single initial dose comprising 100 mg to 300 mg dupilumab”
“..wherein secondary doses comprise 100 mg to 600 mg of dupilumab” (applies to claims 21, 22, 24, 31 and 32).
does not reasonably provide enablement for:
“..wherein dupilumab is administered at a single initial dose comprising 100 mg/kg to 600 mg/kg dupilumab”.
“..wherein the subject is a human adult patient having alopecia areata and dupilumab is administered at a single initial dose comprising 600 mg/kg dupilumab; or the subject is a human child patient having alopecia areata and dupilumab is administered at a single initial dose comprising 100 mg/kg to 300 mg/kg dupilumab”
“..wherein secondary doses comprise 100 to mg/kg to 600 mg/kg of dupilumab” (applies to claims 23, 25-30 and 33)
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.
The specification teaches methods of administering an antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), which can improve the severity of hair loss in a subject that has or is suspected of having alopecia areata (AA). The specification teaches that the antibody or antigen-binding fragment thereof that specifically binds IL-4R includes, for example, dupilumab (paras 0001-0005).
The specification teaches that in some embodiments, the subject may be a human adult patient (e.g., an adult patient having AA). In some embodiments, the subject may be a human child patient (e.g., a child patient having AA). Such a child patient may be younger than 18 years. In some embodiments, a child patient to be treated by the methods disclosed herein may have an age younger than 12, for example, younger than 10, 8, or 6 (para 0092).
The specification teaches that in some embodiments, for an adult patient of normal weight, doses of an anti-IL-4R antibody as described herein (e.g., dupilumab) ranging from about 100 to 600 mg/kg may be administered. In some embodiments, an initial dosage of the anti-IL-4R antibody (e.g., dupilumab) described herein can be about 300 mg/kg for an adult human patient. In some embodiments, an initial dosage can be immediately followed by a secondary dosage of the anti-IL-4R antibody (e.g., dupilumab) described herein, wherein the secondary dosage can be about 300 mg/kg to about 600 mg/kg for an adult human patient. In some embodiments, secondary dosages of an anti-IL-4R antibody as described herein (e.g., dupilumab) can be about 300 mg/kg to about 600 mg/kg for an adult human patient. In some embodiments, an initial dosage of the anti-IL-4R antibody (e.g., dupilumab) described herein can be about 100 mg/kg to 600 mg for a child human patient. In some embodiments, the initial dosage can be immediately followed by a secondary dosage of the anti-IL-4R antibody (e.g., dupilumab) described herein, wherein the secondary dosage can be about 100 mg/kg to about 600 mg/kg for a child human patient. In some embodiments, secondary dosages can be about 100 mg/kg to about 600 mg/kg for a child human patient (para 0101).
The Examples teach that the purpose of this study was to assess whether dupilumab can be a helpful treatment for alopecia areata. The study was a phase 2a, randomized, double-blind, multicenter study with an initial 24-week evaluation period (primary endpoint), followed by another 24-week open-label phase in which all participants were treated with dupilumab up to week 48 (secondary endpoint), with a follow-up to week 72 (para 0124). Patients were randomized 2:1 to receive weekly dupilumab (300 mg) or matching placebo. The primary efficacy endpoint was change from baseline in the Severity of Alopecia Tool (SALT) score at week 24. The SALT score quantifies scalp hair loss, and ranges from 0 (no hair loss) to 100 (complete hair loss)(para 0128). The specification teaches that the inclusion and exclusion criteria for the study were as follows: Inclusion Criteria: Male or female subjects who are at least 18 years old at the time of informed consent (paras 0129-0130).
The Examples teach patients were randomized to receive weekly, subcutaneous dupilumab or matching placebo (300 mg), followed by another 24-week open-label phase in which all participants were treated with weekly dupilumab up to week 48 (secondary endpoint). Patients self-administrated dupilumab/placebo at their home after given instructions and guidance from the research team on baseline visit. From baseline visit to week 48 visit, participants were evaluated every four weeks. After week 48, follow-up continued at weeks 60 and 72 (para 0165). The Examples teach at week 24, worsening of AA was documented in the placebo group, with a least-squares mean change in the SALT score of −6.3, while in the drug arm observed was a least-squares mean change of 2.3, as compared to baseline (paras 0200-0203). The specification teaches that patients achieving SALT.sub.30 had significantly higher baseline IgE levels versus non-responders (338.8, 95% Cl: 0-612.2). Moreover, change in SALT and IgE levels showed a robust and significant correlation both after 48 weeks in the drug arm as well as after 24 weeks of dupilumab treatment in both study arms.
The claims are not enabled for the full scope for the following reasons:
1. The specification never teaches administering dupilumab dose amounts comprising 100 mg/kg to 600 mg/kg to subjects having alopecia areata.
The Examiner understands 600 mg/kg to mean 600 milligrams of dupilumab for every 1 kilogram of body weight. An average adult weighs anywhere from 120 lbs. to 180 lbs. (about 54 to 81 kgs) depending on the sex of the human subject. The weight could be higher depending on the height and/or age of the human subject. Therefore, a male weighing 80 kilograms would have to administer 48,000 mgs of dupilumab (80kg X 600 mg/kg).
The instant specification teaches a child patient to be treated by the methods disclosed herein may have an age younger than 12, for example, younger than 10, 8, or 6. The average 11-year-old is anywhere from 70 to 80 lbs. (about 31 to 36 kgs) depending on sex and height. For example, an 11-year-old child weighing 36 kilograms would have to administer 3,600 mgs of dupilumab (36kg X 300 mg/kg).
The claimed dupilumab amounts of mg/kg result in an extreme amount of the drug being administered. These amounts are not enabled in light of the instant Examples which teach patients received weekly dupilumab dose amounts of 300 mgs. Thus, it cannot be said that the specification provides the proper teaching.
In addition, the prior art teaches administering an initial dupilumab amount of 600 mgs, followed by 300 mgs every over week (Alniemi et al. see below).
Given the guidance, one of ordinary skill in the art could reasonably predict that administering 100 mg to 600 mg of dupilumab would be useful in methods of improving the severity of hair loss in patients having alopecia areata (or suspected of having alopecia areata). However, it could not be predicted what effects the claimed administered amounts would have in subjects.
Due to the inherent unpredictability of delivering dupilumab amounts of 100 mg/kg to 600 mg/kg to subjects having alopecia areata; the lack of direction/guidance presented in the specification regarding same; the absence of working examples directed to same; the complex nature of the invention; and the state of the prior art which establishes dupilumab dose amounts of 300 mg or 600 mg; undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 21, 22 and 24 are rejected under 35 U.S.C. 102 (a1) as being anticipated by Alniemi et al. (Dupilumab treatment for atopic dermatitis leading to unexpected treatment for alopecia universalis. JAAD Case Reports Volume 5:111-2; 2019).
Alniemi et al. teach a case of a dupilumab medication used to treat atopic dermatitis, leading to unexpected treatment for concurrent alopecia areata. Alniemi et al. teach that for the refractory atopic dermatitis, the patient was started on dupilumab, 300 mg subcutaneously, every other week after a loading dose of 600 mg subcutaneously (page 111). Alniemi et al. teach that after starting dupilumab for refractory atopic dermatitis, the patient noted immediate hair regrowth on the scalp. After 8 months of dupilumab use, the patient had a full scalp of hair regrowth, which she lacked for the previous 6 years (page 111)(applies to claims 21, 22 and 24).
Alniemi et al. teach that because atopic dermatitis and alopecia areata have similar robust helper T-cell-mediated cytokine pathways with downstream effects manifesting in the skin, it is understandable that dupilumab, an interleukin (IL)-4 and
IL-13 monoclonal antibody, would have effects on both diseases. Alniemi et al. teach that studies describe the association between these 2 diseases, indicating that IL-4 leads to production of inflammatory mediators such as IgE, mast cells, and eosinophils and that this inflammation is a main factor in disease manifestation. Alniemi et al. teach blocking IL-4, in addition to inflammatory mediator IL-13, therefore, inhibits the downstream effects of inflammation that leads to these 2 pathologic diseases (page 112).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 21, 22, 24, 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Alniemi et al. (Dupilumab treatment for atopic dermatitis leading to unexpected treatment for alopecia universalis. JAAD Case Reports Volume 5:111-2; 2019) in view of Bakry et al. (Total serum immunoglobulin E in patients with alopecia areata. Indian Dermatology Online Journal -Volume 5 - Issue 2; April-June 2014).
Alniemi et al. teach a case of a dupilumab medication used to treat atopic dermatitis, leading to unexpected treatment for concurrent alopecia areata. Alniemi et al. teach that for the refractory atopic dermatitis, the patient was started on dupilumab, 300 mg subcutaneously, every other week after a loading dose of 600 mg subcutaneously (page 111). Alniemi et al. teach that after starting dupilumab for refractory atopic dermatitis, the patient noted immediate hair regrowth on the scalp. After 8 months of dupilumab use, the patient had a full scalp of hair regrowth, which she lacked for the previous 6 years (page 111)(applies to claims 21, 22 and 24).
Alniemi et al. teach that because atopic dermatitis and alopecia areata have similar robust helper T-cell-mediated cytokine pathways with downstream effects manifesting in the skin, it is understandable that dupilumab, an interleukin (IL)-4 and
IL-13 monoclonal antibody, would have effects on both diseases. Alniemi et al. teach that studies describe the association between these 2 diseases, indicating that IL-4 leads to production of inflammatory mediators such as IgE, mast cells, and eosinophils and that this inflammation is a main factor in disease manifestation. Alniemi et al. teach blocking IL-4, in addition to inflammatory mediator IL-13, therefore, inhibits the downstream effects of inflammation that leads to these 2 pathologic diseases (page 112).
. Alniemi et al. teach that studies describe an association between alopecia areata, the production of inflammatory mediators such as IgE. and that this inflammation is a main factor in disease manifestation.
Alniemi et al. do not teach measuring IgE in alopecia areata subjects.
Bakry et al. teach serum levels of total IgE in alopecia areata patients. Bakry et al. teach that subjects with other conditions that might elevate serum IgE were excluded from the study. Bakry et al. teach age- and sex-matched healthy subjects were selected as a control group. Bakry et al. teach blood samples were taken from cases and controls for measurement of total serum IgE by enzyme‑linked immunosorbent assay. Bakry et al. teach that total serum IgE was elevated in 54% cases and that its values among patients ranged from 13.5 IU/ml to 780 IU/ml. Bakry et al. teach that total serum IgE is elevated in alopecia areata (applies to claims 31 and 32).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of treating alopecia areata to improve the severity of hair loss comprising administering an initial dose of dupilumab to a human subject as taught by Alniemi et al., by first measuring total IgE serum in the subject, wherein IgE is a biomarker of alopecia areata, as taught by Bakry et al., wherein the initial dose of dupilumab is administered if the total IgE serum in the subject is elevated compared to a subject not having or not suspected of having alopecia areata and further comprising administering a first secondary dose of dupilumab 5 to 10 days after the initial dose.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons:
Alniemi et al. teach an administered single initial dose of 600 mgs of dupilumab, followed by a first secondary dose (300 mgs) 7 days after the first initial dose treated alopecia areata. Alniemi et al. state that there is an association between alopecia areata, the production of inflammatory mediators such as IgE, and that this inflammation is a main factor in disease manifestation.
Bakry et al. teach serum levels of total IgE in alopecia areata patients compared to a control group. Bakry et al. teach that total serum IgE is elevated in alopecia areata.
Based on the teachings it would be obvious to measure the total IgE serums in subjects having or suspected of having alopecia areata, in order to further confirm the condition before administering dupilumab.
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 5/22/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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