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 .
Election/Restrictions
Applicant’s election without traverse of Species A (i.e., a single and specific patient population as a patient who has type 2 diabetes and Groups 2 pulmonary hypertension); and Species B (i.e., a single and specific ActRII polypeptide as SEQ ID NO: 41 that is fused to an Fc fragment with the linker: TGGG; and a single and specific result as decreasing in fasting glucose levels in the patient to levels less than 100 mg/dL) in the reply filed on April 10, 2026, is acknowledged.
Status of Claims
Claims 1-75 were originally filed on September 7, 2023.
The amendment received on September 7, 2023, canceled claims 2-7, 14, 16-42, 44-55, 64, 66-68, 71-72, and 74-75; and amended claims 1, 8-9, 11-13, 15, 43, 56-59, 61, 63, 65, 69-70, and 73. The amendment received on April 10, 2026, amended claim 1.
Claims 1, 8-9, 11-13, 15, 43, 56-63, 65, 69-70, and 73 are currently pending and claims 1, 9, 11, 43, 56-62, 65, 69-70, and 73 are under consideration as claims 8, 12-13, 15, and 63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 10, 2026.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2022/019583 filed March 9, 2022, and claims priority under 119(e) to U.S. Provisional Application No. 63/159,074 filed on March 10, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 1, 2024, is being considered by the examiner.
Sequence/Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 1, please note that the Examiner is interpreting the scope as open-ended requiring at least 85% identity to an amino acid sequence that begins at any one of amino acids 110-135 of SEQ ID NO: 1 with any N- and/or C-terminal additions. It is noted that SEQ ID NO: 1 is 513 amino acids in length. The specification teaches that residues 1-20 of SEQ ID NO: 1 constitute the signal peptide, and residues 21-135 constitute the extracellular domain of the human ActRII precursor protein (See instant, pg. 20, 2nd paragraph). As discussed in the 112(b) rejection below, the scope of claim 1 is indefinite. The scope of claim 1 encompasses where the amino acid sequence starts within the extracellular domain, i.e., any amino acid from position 110-135. However, the specification does not define the required length of the amino acid sequence, but rather only which residue the sequence starts at. As such, the amino acid sequence encompasses 85% identity to a sequence as small as a dipeptide, e.g., residues 110-111 of SEQ ID NO: 1, up to an amino acid sequence ranging from residues 110-513 thereby including up to 61 amino acid modifications such as substitutions, deletions and/or insertions. Alternatively, the scope of claim 1 encompasses where the amino acid sequence contains a fragment that is at least 85% identical where the fragment starts at any amino acid at position 110-135. As such, the amino acid sequence comprises SEQ ID NO: 1 that is 100% identical to residues 1-109 of SEQ ID NO: 1, but encompasses up to 61 amino acid modifications such as substitutions, deletions and/or insertions (i.e., between residues 110-513).
Additionally, for claim 1, it is noted that “treating” is defined to generally mean obtaining a desired pharmacologic and/or physiologic effect, and can be used to refer to improving, alleviating and/or decreasing the severity of one or more clinical complications of a condition being treated (See instant, pg. 43, last paragraph). The effect can be prophylactic in terms of completely or partially delaying the onset or recurrence of a disease, condition, or complications thereof and/or can be therapeutic in terms of a partial or complete cure for a disease or condition and/or adverse effect attributable to the disease or condition (See instant, pg. 43, last paragraph). The specification also defines “a patient in need thereof” as a patient in need of treatment with an ActRII polypeptide and having a disorder or condition disclosed, i.e., hyperglycemia associated with pulmonary hypertension, in this case (See instant, pg. 44, 1st paragraph). Thus, since the scope of claim 1 requires that the ActRII polypeptide be administered to a patient in need thereof of treatment of hyperglycemia associated with PH, it would then follow that the patient must already have hyperglycemia associated with PH. As such, prophylactic treatment encompassing complete delay of the onset of hyperglycemia associated with PH is not encompassed by the claimed invention. Therefore, the scope of the claimed invention does not encompass 100% prevention.
For claim 56, please note that the Examiner is interpreting the scope as open-ended requiring at least 90% identity to residues 30-110 of SEQ ID NO: 1 with any N- and/or C-terminal additions. Residues 30-110 constitutes 80 residues thereby encompassing up to 8 amino acid modifications such as substitutions, deletions and/or insertions. However, the scope of claim 56 encompasses 100% identity to residues 1-29 and 111-513 of SEQ ID NO: 1, which as further articulated below, conflicts with the interpretation of claim 1.
For claim 57, please note that the Examiner is interpreting the scope as open-ended requiring at least 85% identity to SEQ ID NO: 2 (i.e., corresponds to residues 21-135 of SEQ ID NO: 1 and residues 1-115 of elected SEQ ID NO: 41) with any N- and/or C-terminal additions. It is noted that SEQ ID NO: 2 is 115 amino acids in length thereby encompassing up to 17 amino acid modifications such as substitutions, deletions and/or insertions.
For claim 58, please note that the Examiner is interpreting the scope as open-ended requiring at least 85% identity to SEQ ID NO: 3 (i.e., corresponds to residues 21-120 of SEQ ID NO: 1 and residues 1-100 of elected SEQ ID NO: 41) with any N- and/or C-terminal additions. It is noted that SEQ ID NO: 2 is 100 amino acids in length thereby encompassing up to 15 amino acid modifications such as substitutions, deletions and/or insertions.
For claim 62, please note that the Examiner is interpreting the scope as open-ended requiring 100% identity to one of the recited sequences with any N- and/or C-terminal additions.
For claim 65, please note that the Examiner is interpreting the scope of as open-ended requiring at least 90% identity to SEQ ID NO: 41 (i.e., corresponds to residues 21-115 of SEQ ID NO: 1) with any N- and/or C-terminal additions. It is noted that SEQ ID NO: 41 is 343 amino acids in length thereby encompassing up to 34 amino acid modifications such as substitutions, deletions and/or insertions.
Drawings
The drawings; in particular, Figures 1-2, are objected to because of the following reason:
The drawings have a line quality that is too light to be reproduced (weight of all lines and letters must be heavy enough to permit adequate reproduction) or text that is illegible (reference characters, sheet numbers, and view numbers must be plain and legible, i.e., the amino acid residues) see 37 CFR 1.84(l) and (p)(1)); See Figure(s) 1-2.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1, 57-59, 61, 65, 69-70, and 73 are objected to because of the following informalities: claim 1 recites, “…an effective amount of an ActRII polypeptide…” Although, the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner respectfully requests that Applicant uses activin A receptor type II (ActRII) for the first recitation, thereafter ActRII may be utilized. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 9, 11, 43, 56-62, 65, 69-70, and 73 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 includes an “ActRII polypeptide comprising at least 85% identity to an amino acid sequence that begins at any one of amino acids 110-135 of SEQ ID NO: 1”; dependent claim 56 includes an “ActRII polypeptide comprising at least 90% identity to the sequence of amino acids corresponding to residues 30-110 of SEQ ID NO: 1”; dependent claim 57 includes an “ActRII polypeptide comprising at least 85% identity to the amino acid sequence SEQ ID NO: 2”; dependent claim 58 includes an “ActRII polypeptide comprising at least 85% identity to the amino acid sequence of SEQ ID NO: 3”; and dependent claim 65 include an “ActRII polypeptide comprising at least 90% identity to the amino acid sequence SEQ ID NO: 41”. It is noted that SEQ ID NO: 1 is the canonical human ActRIIA precursor protein sequence and is 513 amino acids in length. The specification teaches that residues 1-20 of SEQ ID NO: 1 constitute the signal peptide, and residues 21-135 constitute the extracellular domain of the human ActRII precursor protein (See instant, pg. 20, 2nd paragraph). The interpretation of claim 1 is described above in the “Sequence Interpretation” section and in the 112(b) rejections below where the Examiner is interpreting the ActRII polypeptide as requiring 100% identity to residues 1-109 of SEQ ID NO: 1, but encompasses up to 61 amino acid modifications such as substitutions, deletions and/or insertions (i.e., between residues 110-513). Furthermore, the interpretation includes where the ActRII polypeptide requires residues 1-109 but only requires a dipeptide, e.g., residues 110-111, a fragment with a single deleted residue at residue at the C-terminus, e.g., residue 513 deleted, and a fragment that contains residues 110-513 but with 61 substitutions. Moreover, it is noted that SEQ ID NO: 2 represents the mature extracellular human ActRIIA polypeptide sequence, i.e., residues 21-135 of SEQ ID NO: 1, and is 115 total amino acids length. SEQ ID NO: 3 is a truncated fragment of SEQ ID NO: 2 where the 15 most C-terminal residues are deleted, i.e., residues 21-120 of SEQ ID NO: 1, and is 100 total amino acids in length. SEQ ID NO: 41 is a fusion protein comprising SEQ ID NO: 2, a TGGG linker sequence, and a Fc domain of an IgG1 immunoglobulin, i.e., residues 21-115 of SEQ ID NO: 1, and is 343 total amino acids in length. The interpretation of each of claims 56-58 and 65 is described above in the “Sequence Interpretation” section supra. The ActRII polypeptide also must exhibit the function of treating hyperglycemia associated with pulmonary hypertension (PH) by decreasing fasting glucose levels in a patient to levels less than 100 mg/dL, and exhibit the function of binding to one or more ligands selected from Activin A, Activin B, and GDF11. Thus, the scope of the claimed invention encompasses a vast array of ActRII polypeptide sequences without a clearly defined core structure or sequence necessary to exhibit the claimed functions.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, the kinase ActRII binds multiple ligands, with high affinity to activins, GDF11 and BMP10 (Lodberg, Cytokine Growth Factor Rev. 2021 Aug;60:1-17, Pg. 6, Left column, 4.3. Actvin type IIA decoy receptors, paragraph 2, Lines 1-4). Lodberg teaches the ActRIIA-Fc decoy receptor, sotatercept. The sotatercept ligand binding moiety is identical to the native ActRIIA receptor with a single amino-terminal truncation (Pg. 6, Right column, full paragraph 1, entire paragraph). It is noted that sotatercept is 100% identical to instant SEQ ID NO: 41. As such, the art recognizes a ActRIIA ECD-Fc domain fusion protein where the ActRIIA portion is 100% identical to instant SEQ ID NO: 2. Pertaining to the structural basis of ActRIIA binding to the ligand activin A, Gray (J Biol Chem. 2000 Feb 4;275(5):3206-12) teaches three interacting hydrophobic residues in the ActRIIA ECD - Phe42, Trp60, and Phe83 (Pg. 3209, Right column, Lines 1-8, Table I). Gray shows that F42A, W60A, and F83A mutant receptors expressed on the surface of corticotroph cells have abolished activin A/TGFβ signaling (Pg. 3210, Right column, Lines 1-6, and Fig. 4). In contrast, the K56A mutation which is adjacent to the Phe42-Trp60-Phe83 binding interface does not influence activin A binding (Pg. 3210, Right column, Lines 10-15, and Table I). Furthermore, the art teaches other mutations that alter selectivity of ActRIIA to its different ligands. WO2006/012627 teaches certain mutations increase selectivity for GDF11 over activin (K74Y,
K74F, K74I and D80I), others increase selectivity for activin over GDF11 (D54A, K55A, L 79A and F82A) and others reduce ligand binding overall, teaching that mutations may be combined to achieve desired effects (Pg. 4, Lines 5-14). In the instant case, the prior art does not provide guidance as to which mutations would necessarily produce the claimed therapeutic benefit of the recited methods. Therefore, although the art teaches critical residues for ligand binding, with different residues determining selectivity for the different ligands, the art fails to provide what structures must be maintained in the claimed fragments and mutated variants of the native ActRIIA in order to maintain the claimed functions. Thus, the claims are directed to ActRII polypeptides with certain functions but no correlated structure associated with those functions. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches that ActRII is well-conserved among vertebrates, which large stretches of the extracellular domain completely conserved (See instant, pg. 22, 2nd paragraph). Many of the ligands that bind to ActRII are also highly conserved (See instant, pg. 22, 2nd paragraph). Figure 1 depicts an alignment of the amino acid sequences of human ActRIIA extracellular domain and human ActRIIB extracellular domain where the composite structures indicate that the ActRIIA-ligand binding pocket is defined, in part, by residues F31, N33, N35, K38 through T41, E47, Y50, K53 through K55, R57, H58, F60, T62, K74, W78 through N83, Y85, R87, E92, and K94 through F101 (See instant, pg. 22, 3rd paragraph). Moreover, the specification teaches that a defining structural motif known as a three-finger toxin is important for ligand binding by type I and type II receptors and is formed by conserved cysteine residues located at varying positions within the extracellular domain of each monomeric receptor (See instant, pg. 23, 3rd paragraph). As such, the core ligand-binding domains of human ActRII, as demarcated by the outermost of these conserved cysteines, corresponds to positions 30-110 of SEQ ID NO: 1 (See instant, pg. 23, 3rd paragraph). Therefore, the structurally less-ordered amino acids flanking these cysteine-demarcated core sequences can be truncated from about 1-29 residues at the N-terminus and by about 1-25 at the C-terminus without necessarily altering ligand binding (See instant, pg. 23, 3rd paragraph). Exemplary ActRII ECD truncations include SEQ ID NO: 2 and 3 (See instant, pg. 23, 3rd paragraph). Thus, a general formula for an active portion, e.g., ligand binding, of ActRII is a polypeptide that comprises amino acids 30-110 of SEQ ID NO: 1, i.e., SEQ ID NO: 3 (See instant, pg. 23, last paragraph). However, as discussed in the “Sequence Interpretation” section supra, the scope of claims 56-58 and 65 encompass variability within this core structure identified as being critical for the ActRII polypeptide to exhibit the function of ligand binding. Furthermore, the specification in Examples 4-5 only demonstrates that instant SEQ ID NO: 41 (i.e., residues 21-135 of SEQ ID NO: 1 fused to a Fc domain) exhibited the function treating hyperglycemia associated with pulmonary hypertension (PH) by decreasing fasting glucose levels in a patient to levels less than 100 mg/dL. Thus, the specification not sufficient for the skilled artisan to envisage what modifications to instant SEQ ID NO: 41 including at residues 21-135 of SEQ ID NO: 1 can be modified with the expectation that the claimed functions will be preserved.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, what is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 1, 9, 11, 43, 56-62, 65, 69-70, and 73 do not meet the written description requirement.
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 1, 9, 11, 43, 56-62, 65, 69-70, and 73 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. Claim 1 is direct to administering an effective amount of an ActRII polypeptide comprising an amino acid sequence that is at least 85% identical to an amino acid sequence that begins at any one of amino acids 110-135 of SEQ ID NO: 1. As such, claim 1 has multiple interpretations rendering the scope of claim 1 indefinite. The first interpretation is that the ActRII amino acid sequence comprises SEQ ID NO: 1 and within SEQ ID NO: 1 there is a portion (i.e., fragment) that is at least 85% identical to an amino acid sequence that begins with one of the amino acids at positions 110-135 of SEQ ID NO: 1. In other words, there is 100% identity to residues 1-109, but 85% identity to a fragment that starts at any one of residues 110-135. However, there is no limit to the fragment size, e.g., a dipeptide such as residues 110-111, a fragment ranging from residues 110-200, or a fragment ranging from residues 110-513. As such, the ActRII amino acid sequence encompasses SEQ ID NO: 1, i.e., SEQ ID NO: 1 contains a fragment containing 100% identity to the amino acids beginning at positions 110-135 of SEQ ID NO: 1. The second interpretation is that the ActRII amino acid sequence is to start at any one of the amino acids at positions 110-135 of SEQ ID NO: 1. This interpretation would correspond to the ActRII amino acid sequence not being capable of having any residues that are N-terminal to the amino acid at position 110 of SEQ ID NO: 1 thereby excluding SEQ ID NO: 1 as the ActRII amino acid sequence. As such, the ActRII amino acid sequence could not contain residues 1-109 of SEQ ID NO: 1, but rather can only contain a fragment, e.g., a dipeptide such as residues 110-111, a fragment ranging from residues 110-200, or a fragment ranging from residues 110-513. Given the multiple interpretations of claim 1, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the claimed invention with respect to the ActRII amino acid sequence.
Please note that the Examiner is interpreting the scope of claim 1 such that the first interpretation applies in order to advance prosecution. Also please note that claims 9, 11, 43, 57-62, 65, 69-70, and 73 are rejected by virtue of their dependency.
Claims 56 and 59-62 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. Claim 56 recites, “wherein the ActRII polypeptide an amino acid sequence that is…” It appears a transitional phrase is missing between “ActRII polypeptide” and “an amino acid sequence”. As such, it is unclear which transitional phrase is intended to be utilized. Thus, an ordinary skilled artisan would be unable to ascertain the metes and bounds of the claimed invention with respect to the transitional phrase in claim 56.
Please note that the Examiner is interpreting the scope of claim 56 such that the transitional phrase is “comprises” in order to advance prosecution. Also please note that claims 59-62 are rejected by virtue of their dependency.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 56 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 56 is directed to where the ActRII polypeptide comprises an amino acid sequence that is at least 90% identical to the sequence of amino acids corresponding to residues 30-100 of SEQ ID NO: 1. As discussed in the “Sequence/Claim Interpretation” section supra, the scope of claim 56 encompasses 100% identity to residues 1-29 and 111-513 of SEQ ID NO: 1, but at least 90% identity to residues 30-110 thereby encompassing up to 8 amino acid modifications such as substitutions, deletions and/or insertions. However, given that the first interpretation of claim 1 is being applied (See 112(b) rejection supra), claim 56 would not be able to contain variability at the residues ranging from 30-109 of SEQ ID NO: 1. As such, the 90% variability of SEQ ID NO: 1 in claim 56 would only apply to residue 110 of SEQ ID NO: 1, but currently encompasses 90% variability of a fragment of 80 residues of SEQ ID NO: 1. Thus, the scope of claim 56 broadens the scope of claim 1 when utilizing the first interpretation of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 57 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 57 is directed to where the ActRII polypeptide comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 2. As discussed in the “Sequence/Claim Interpretation” section supra, SEQ ID NO: 2 corresponds to residues 21-135 of SEQ ID NO: 1. However, given that the first interpretation of claim 1 is being applied (See 112(b) rejection supra), claim 57 would not be able to contain variability at the residues ranging from positions 21-109 of SEQ ID NO: 1. Rather, claim 1 encompasses sequence variability starting at residue 110 of SEQ ID NO: 1. As such, the 85% variability of SEQ ID NO: 2 in claim 57 would only apply to residues 90-115 of SEQ ID NO: 2, but currently encompasses 85% variability of SEQ ID NO: 2 as a whole. Thus, the scope of claim 57 broadens the scope of claim 1 when utilizing the first interpretation of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 58 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 58 is directed to where the ActRII polypeptide comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 3. As discussed in the “Sequence/Claim Interpretation” section supra, SEQ ID NO: 3 corresponds to residues 21-120 of SEQ ID NO: 1. However, given that the first interpretation of claim 1 is being applied (See 112(b) rejection supra), claim 58 would not be able to contain variability at the residues ranging from positions 21-109 of SEQ ID NO: 1. Rather, claim 1 encompasses sequence variability starting at residue 110 of SEQ ID NO: 1. As such, the 85% variability of SEQ ID NO: 3 in claim 58 would only apply to residues 91-100 of SEQ ID NO: 3, but currently encompasses 85% variability of SEQ ID NO: 3 as a whole. Thus, the scope of claim 58 broadens the scope of claim 1 when utilizing the first interpretation of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 65 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 65 is directed to where the ActRII polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 41. As discussed in the “Sequence/Claim Interpretation” section supra, SEQ ID NO: 41 corresponds to residues 21-135 of SEQ ID NO: 1. However, given that the first interpretation of claim 1 is being applied (See 112(b) rejection supra), claim 65 would not be able to contain variability at the residues ranging from positions 21-109 of SEQ ID NO: 1. Rather, claim 1 encompasses sequence variability starting at residue 110 of SEQ ID NO: 1. As such, the 85% variability of SEQ ID NO: 41 in claim 65 would only apply to residues 91-115 of SEQ ID NO: 41, but currently encompasses 85% variability of SEQ ID NO: 41 as a whole. Thus, the scope of claim 65 broadens the scope of claim 1 when utilizing the first interpretation of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1, 9, 11, 43, 56-62, 65, 69-70, and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Kumar et al. WO 2018/013936 A1 published on January 18, 2018, in view of Kumar et al. WO 2018/067879 A1 published on April 12, 2018 (cited in the IDS received on 2/1/24), and Pugh et al., Int. J. Clin. Pract. Suppl. 64:5-13 (2010).
For claims 1, 43, 56-62, 65, and 69, with respect to a method of treating hyperglycemia associated with pulmonary hypertension by administering to a patient in need thereof an effective amount of an ActRII polypeptide comprising SEQ ID NO: 41 as recited in instant claims 1, 56-62, and 65; with respect to where the patient further has type 2 diabetes as recited in instant claim 43; and with respect to where the ActRII polypeptide binds to activin A, activin B, and/or GDF11 as recited in instant claim 69:
‘936 teaches methods for treating pulmonary hypertension (PH), e.g., PAH, and one or more complications of PH to a patient in need thereof an effective amount of an GDF/BMP antagonist such as an ActRIIA polypeptide, an ALK4:ActRIIB heterodimer, or an antibody that binds to ActRIIA and/or ActRIIB (See ‘936, pg. 2, last paragraph to pg. 5, last paragraph; pg. 27, last paragraph to pg. 28, 1st paragraph; pg. 40, last paragraph to pg. 41, 2nd paragraph; pg. 43, last paragraph to pg. 44, 1st paragraph; pg. 90, last paragraph; pg. 132, 1st paragraph; pg. 134, last paragraph; pg. 135, 4th paragraph; pg. 136, last paragraph; pg. 137, last paragraph). The ActRIIA polypeptides bind to one or more ligands selected from activin A, activin B, GDF11, GDF8, BMP10 and BMP6 (See ‘936, pg. 6, 1st paragraph; pg. 151, 3rd paragraph) thereby satisfying the claim limitation with respect to where the ActRII polypeptide binds to activin A, activin B, and/or GDF11 as recited in instant claim 69. The ActRIIA polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NOs: 9-11, 32, 36, or 39 (See ‘936, pg. 17, last paragraph to pg. 18, 1st paragraph; pg. 25, last paragraph to pg. 26, 1st paragraph; pg. 54, 2nd paragraph to pg. 60, 1st paragraph; pg. 83, 3rd paragraph; pg. 149, last paragraph to pg. 150, 1st paragraph). When comparing ‘936 SEQ ID NO: 32 with instant SEQ ID NO: 41, there is 100% identity where ‘936 SEQ ID NO: 32 has an added lysine residue at the C-terminus, i.e., ‘936 SEQ ID NO: 32 is 344 total amino acids whereas instant SEQ ID NO: 41 is 343 total amino acids. As such, ‘936 SEQ ID NO: 32 constitutes the ActRII polypeptide as recited in instant claims 1, 56-62, and 65. Therefore, ‘936 is suggestive of a method of treating PH by administering to a patient in need thereof an effective amount of an ActRII polypeptide comprising instant SEQ ID NO: 41 as recited in instant claims 1, 56-62, and 65.
However, ‘936 does not expressly teach that the treatment is for hyperglycemia associated with PH as recited in instant claim 1 and where the patient further has type 2 diabetes as recited in instant claim 43.
‘879 teaches that an ALK4:ActRIIB heterodimer can be used to treat a disease or condition that is associated with abnormal activity of an ALK4:ActRIIB-binding ligand where these diseases or conditions are referred to as “ALK4:ActRIIB-associated conditions” or “ALK4:ActRIIB-associated disorders” (See ‘879, pg. 101, last paragraph). As such, ‘879 teaches method of treating an ALK4:ActRIIB-associated condition in an individual by administering to the individual in need thereof a therapeutically effective amount of an ALK4:ActRIIB heteromultimer (See ‘879, pg. 101, last paragraph to pg. 102, 1st paragraph). Heteromultimers includes heterodimers that can bind to activin A (See ‘879, pg. 53, 1st paragraph). As such, the ‘879 ALK4:ActRIIB heterodimers are the same as the ‘936 ALK4:ActRIIB heterodimers thereby functioning as GDF/BMP antagonists. Particular methods of treating ALK4:ActRIIB-associated conditions include treating PH or PAH by administering to a patient in need thereof an effective amount of an ALK4:ActRIIB heteromultimer (See ‘879, pg. 40, last paragraph to pg. 44, 1st paragraph; pg. 55, 1st paragraph to ; pg. 128, 2nd paragraph to pg. 134, 2nd paragraph). Another particular method of treatment includes treatment of a disorder or condition such as hyperglycemia or a disease or condition associated with hyperglycemia in a subject who has type 2 diabetes (See ‘879, pg. 113, last paragraph to pg. 114, 2nd paragraph; pg. 118, 2nd to last paragraph; pg. 120, 2nd paragraph to pg. 121, 2nd paragraph). ‘879 also teaches a method of treating type 2 diabetes or a disease or condition associated with diabetes by administering to a subject in need thereof an effective amount of an ALK4:ActRIIB heteromultimer (See ‘879, pg. 117, 2nd paragraph). Moreover, ‘879 teaches that metabolic syndrome is a condition involving a set of disorders that enhances the risk of heart disease where the major components of metabolic syndrome include diabetes (See ‘879, pg. 119, 2nd paragraph). Therefore, ‘879 teaches methods of treating an ALK4:ActRIIB-associated condition such as diabetes, hyperglycemia, PH, and PAH by administering to a subject in need thereof an effective amount of an ALK4:ActRIIB heterodimer.
However, ‘879 does not expressly teach hyperglycemia as a condition associated with PH.
Pugh et al. teaches that recent animal and human studies have highlighted abnormalities in regulation and metabolism of insulin that may play a role in PAH development (See Pugh, abstract). Moreover, Pugh et al. teaches that in humans, insulin resistance, the metabolic syndrome (MS), and low levels of high-density lipoprotein have been associated with PAH (See Pugh, abstract; pg. 1, 1st paragraph). Pugh et al. found that there is a strong female predominance in PAH patients, and co-morbid conditions including features of metabolic syndrome were common including diabetes in 12% (See Pugh, pg. 2, 1st paragraph). Thus, PAH is commonly accompanied by features of the metabolic syndrome (See Pugh, pg. 2, 1st paragraph). The metabolic syndrome is a group of metabolic and biochemical risk factors for developing cardiovascular disease and diabetes where one core feature of MS include dysglycemia (See Pugh, pg. 2, 2nd paragraph). Pugh et al. notes that 56% of PAH patients without a prior diagnosis of diabetes had glucose intolerance (a HbA1c ≥ 6%) (See Pugh, pg. 5, last paragraph). Thus, Pugh et al. demonstrates that metabolic syndrome, insulin resistance, and hyperglycemia (i.e., glucose intolerance (a HbA1c ≥ 6%)) are associated with PAH.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to combine the teachings of ‘936 and ‘879 in light of Pugh et al. and administer an effective amount of an ActRIIA polypeptide comprising instant SEQ ID NO: 41 instead of an ALK4:ActRIIB heterodimer as an GDP/BMP antagonist to a patient who has type 2 diabetes in order to treat hyperglycemia that is associated with PAH. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because GDP/BMP antagonists such as an ActRIIA polypeptide comprising instant SEQ ID NO: 41 and ALK4:ActRIIB heterodimers were known to be administered in an effective amount to treat PAH in a patient as taught by ‘936; because ALK4:ActRIIB heterodimers were known to be administered in an effective amount to treat PAH, metabolic syndrome, or hyperglycemia in a patient as taught by ‘879; and because metabolic syndrome, insulin resistance, and hyperglycemia (i.e., glucose intolerance (a HbA1c ≥ 6%)) were known to be associated with PAH as taught by Pugh et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that GDF/BMP antagonists of ‘936 include an ActRIIA polypeptide comprising instant SEQ ID NO: 41 and ALK4:ActRIIB heterodimers and administered in an effective amount to treat PAH in a patient. Therefore, administering an effective amount of an ActRIIA polypeptide comprising instant SEQ ID NO: 41 instead of an ALK4:ActRIIB heterodimer would support the treatment of hyperglycemia associated with PAH given that metabolic syndrome, insulin resistance, and hyperglycemia (i.e., glucose intolerance (a HbA1c ≥ 6%)) were known to be associated with PAH by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
For claim 9, with respect to where the pulmonary hypertension is Group 2 pulmonary hypertension:
‘936 teaches that PH has been classified into 5 Groups where Group 2 is PH with left heart disease (See ‘936, pg. 135, 3rd paragraph). ‘936 thus teaches methods of treating or reducing the progression rate and/or severity of PH by administering to a patient in need thereof an effective amount of a GDF/BMP antagonist where the patient have PH with left heart disease (i.e., Group 2 PH) (See ‘936, pg. 135, 4th paragraph). Therefore, the teachings of ‘936 satisfy the claim limitation as recited in instant claim 9.
For claim 11, with respect to where administration of the polypeptide results in a decrease in fasting glucose levels in the patient to less than 100 mg/dL:
As discussed supra, ‘879 teaches a method of treating hyperglycemia by administering an effective amount of an ALK4:ActRIIB heteromultimer to a patient in need thereof. ‘879 also teaches that hyperglycemia is > 130 mg/dL in the fasting state or following glucose administration during an oral glucose tolerance test (See ‘879, pg. 118, last paragraph; pg. 120, 2nd paragraph to pg. 121, 2nd paragraph). In one embodiment, the subject is administered has a postprandial blood sugar level of >180 mg/dL 2 hours after eating (See ‘879, pg. 120, 2nd paragraph to pg. 121, 2nd paragraph). In treating hyperglycemia or a condition associated with hyperglycemia, ‘879 teaches that such treatment includes a decrease in serum levels of glucose (See ‘879, pg. 120, last paragraph to pg. 121, 1st paragraph). Since hyperglycemia is indicative at glucose levels above 130 mg/dL, treatment of hyperglycemia by administering an effective amount of an ALK4:ActRIIB heteromultimer would result in a decrease in serum glucose levels below 130 mg/dL.
MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, as discussed supra, ‘936 teaches methods of treating PH by administering an effective amount of a GDF/BMP antagonist such as a ActRIIA polypeptide comprising instant SEQ ID NO: 41 or an ALK4:ActRIIB heterodimer to a patient in need thereof thereby demonstrating that instant SEQ ID NO: 41 and ALK4:ActRIIB heterodimers function similarly as GDF/BMP antagonists for the treatment of PH. Plus, 879 teaches methods of treating hyperglycemia or PH by administering an effective amount of an ALK4:ActRIIB heterodimer. Thus, as discussed supra, an ordinary skilled artisan would substitute the ActRIIA polypeptide comprising instant SEQ ID NO: 41 instead of an ALK4:ActRIIB heterodimer given that both function similarly as GDF/BMP antagonists to treat hyperglycemia. ‘879 also teaches that treatment of hyperglycemia would result in a decrease in fasting glucose levels in the patient below 130 mg/dL.
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants’ administered ActRII polypeptide differs, and if so to what extent, from the administered ActRII polypeptide suggested by ‘936 and ‘879. The cited art taken as a whole demonstrates a reasonable probability that the suggested administered ActRII polypeptide is either identical or sufficiently similar to the claimed administered ActRII polypeptide that whatever differences exist are not patentably significant. Therefore, with the showing of the reference, the burden of establishing non-obviousness by objective evidence is shifted to the Applicants.
Merely because a property of an administered ActRII polypeptide is not expressly taught in a reference does not make the known administered ActRII polypeptide patentable. The administered ActRII polypeptide possesses properties necessarily present which might not be displayed in the tests used in ‘936 or ‘879. Accordingly, the disclosures of ‘936 and ‘879 are a sufficient basis that the suggested administered ActRII polypeptide would result in a decrease in fasting glucose levels in the patient to levels less than 100 mg/dL.
In the alternative, even if the claimed administered ActRII polypeptide is not identical to the suggested administered ActRII polypeptide with regard to some unidentified properties, the differences between that which is taught and that which is claimed are considered to be so slight that the suggested administered ActRII polypeptide is likely to inherently possess the same properties of the claimed administered ActRII polypeptide particularly in view of the similar structural characteristics which they have been shown to share. Thus, the claimed administered ActRII polypeptide would have been obvious to those of ordinary skill in the art under the meaning of USC 103. Accordingly, the claimed invention as a whole was at least prima facie obvious, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
For claim 70, with respect to where the ActRII polypeptide is administered at a dose between 0.1 mg/kg and 2.0 mg/kg:
‘936 teaches that SEQ ID NO: 32 was very stable in pharmacokinetic studies (See ‘936, pg. 151, last paragraph). Rats were dosed with 1 mg/kg, 3 mg/kg, or 10 mg/kg of SEQ ID NO: 32 and the plasma levels of the protein were measured at 24, 48, 72, 144, and 168 hours (See ‘936, pg. 151, last paragraph). In a separate study, rats were dosed at 1 mg/kg, 10 mg/kg, or 30 mg/kg where SEQ ID NO: 32 had an 11-14 day serum half-life and circulating levels of the drug were quire high after 2 weeks (See ‘936, pg. 151, last paragraph). Thus, ‘936 demonstrates that a dosage of SEQ ID NO: 32 of 1 mg/kg is sufficient for achieving intended efficacy.
MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed dosage range of the ActRII polypeptide would have been obvious to one of ordinary skill in the art since the prior art dosage (i.e., 1 mg/kg) lies within the claimed dosage range (i.e., 0.1 mg/kg to 2 mg/kg).
For claim 73, with respect to where the ActRII polypeptide is administered to the patient every week, every two weeks, every three weeks or every four weeks:
‘936 teaches that dosing of the GDF/BMP antagonists can be adjusted based on measurement of hematologic parameters (See ‘936, pg. 144, 2nd paragraph). For example, if administration of one or more GDF/BMP antagonists results in an increase in blood pressure, red blood cell level, or hemoglobulin level, or a reduction in iron stores, then the dose of the one or more antagonists can be reduced in amount or frequency in order to decrease the effects of the one or more antagonists on the one or more hematologic parameters (See ‘936, pg. 144, 2nd paragraph). Moreover, ‘936 teaches that the dosage regimen will be determined by the attending physician considering various factors which modify the action of the ActRIIA polypeptides (See ‘936, pg. 148, 1st paragraph). Plus, as discussed supra for claim 70, ‘936 demonstrates that 1 mg/kg of SEQ ID NO: 32 had a half-life of 11-14 days thereby suggestive of administration weekly to biweekly. Thus, ‘936 teaches that the dosage and/or frequency of administration of the ActRIIA polypeptide can be adjusted as needed depending on the individual effect on the patient.
The administration frequency of the ActRIIA polypeptide is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal administration frequency of the ActRIIA polypeptide needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to adjust the administration frequency of the ActRIIA polypeptide as suggested by ‘936, for treating PH or one or more complications of PH, because an ordinary skilled artisan would have been able to utilize the teachings of ‘936 to obtain various administration frequency parameters such as weekly, biweekly, tri-weekly, etc. with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the administration frequency of the ActRIIA polypeptide would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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