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 .
Applicant’s arguments filed on 8/18/2025 have been entered.
Claims 1-7 are examined in the instant application.
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.
Claim(s) 1-7 remain rejected under 35 U.S.C. 103 as being unpatentable over Bernstein et al. (US 2015/0353890) in view of Kodama et al. (1991, J. Exp. Med., Vol. 173, pgs. 269-272) and de Souza et al. (2017, World J. Gastroenterology, Vol. 23(28), pgs. 5146-5157) and further evidenced by the teachings of Wu et al. (2017, J. Clin. Endocrinol. Metab., Vol. 102(9), pgs. 3111-3123) and Motyckova et al. (2001, PNAS, Vol. 98(10), pgs. 5798-5803) for reasons of record in the Non-Final Office Action mailed on 8/18/2025 (and repeated below).
Regarding claims 1 and 4-6, Bernstein et al. teach a method of treating osteopetrosis in a human subject comprising the infusion of hematopoietic stem cells (HSC) (see Table 2, parags. 198, 207, 212 and 219).
Bernstein continues to teach that the administered HSC can differentiate into monocytic cells by teaching that their HSC can (emphasis added) “differentiate into (i) myeloid progenitor cells, which myeloid progenitor cells ultimately give rise to monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells, or (ii) lymphoid progenitor cells, which lymphoid progenitor cells ultimately give rise to T-cells, B-cells, and lymphocyte-like cells called natural killer cells (NK-cells ).” (parag. 8 lines 6-13).
Bernstein continues to teach that cells differentiated from HSC can also be delivered to treat osteopetrosis (parag. 148).
Regarding claims 2 and 3, the teachings of Wu et al. are relied upon in teaching that the decreased expression of CA2 (aka CAII) and phenotypes such as hypocalcemia are inherent to osteopetrosis (see Table 2 and pg. 3113 Genetic Testing bridge pg. 3114).
Regarding claim 7, the teachings of Motyckova et al. relied upon in teaching that subjects with osteopetrosis have a cathepsin K deficiency (see Abstract and Results and Discussion).
Bernstein does not teach:
(i) using monocytic cells, and
(ii) administering monocytic cells.
(i) Regarding monocytic cells and osteopetrosis, Kodama et al. teach that in an osteopetrosis mouse model administered recombinant human M-CSF (rhM-CSF), monocyte levels were increased 2 to 3 times (see Abstract).
Kodama teaches that “Mice homozygous for the recessive osteopetrosis mutation
(op/op) have a severe deficiency of osteoclasts, monocytes, and peritoneal macrophages (1-3).” (pg. 269 col. 1 lines 1-3).
Kodama teaches that “we examined whether the osteoclast deficiency in op/op mice could be cured by an exogenous supply of purified human recombinant M-CSF (rhM-CSF). We found that this deficiency, as well as that of monocytes in the peripheral blood, was completely
cured by daily injections of the rhM-CSF for 14 d.” (pg. 269 col. 1 last line bridge col. 2 lines 1-5).
Importantly, Kodama teaches that:
(i) “osteopetrosis in the long bones of op/op mice was completely cured by only
one injection of rhM-CSF per day. Bone trabeculae in the diaphyses were removed. Many osteoclasts were detected on the surface of bone trabeculae in the metaphyses.” (Abstract lines 7-9); and
(ii) (emphasis added) “Our present study demonstrates that the deficiency in osteoclasts and monocytes in op/op mice is caused by the absence of functional M-CSF. Interestingly, osteoclasts in different bones and monocytes in peripheral blood showed different responsiveness to the rhM-CSF injections. Osteoclasts appearing in response to the rhM-CSF injections showed a distribution similar to that observed in normal mice and actively participated in physiological bone remodeling.” (pg. 272 col. 1 lines 1-8).
Thus, Kodama teaches that it is osteoclasts, which are produced from monocytes, which are responsible for the observed curing of osteopetrosis.
(ii) Regarding administering monocytic cells, de Souza et al. teach that at the time of filing it was obvious to administer monocytes for therapeutic treatment. Specifically, de Souza teaches that infusing bone marrow derived monocytes into a mouse model of chronic liver damage (see Abstract, pg. 5149 col. 1 parag. 2) was successful in treating liver fibrosis by regulating important cytokines involved in the liver repair process (see Discussion).
Regarding the new limitations that the claimed method does not comprise HSC transplantation and does not result in HSC chimerism, this would be obvious in view of the teachings of de Souza regarding administering only monocytic cells. If only monocytic cells are administered then no HSC transplantation or HSC chimerism will occur.
Thus, at the time of filing the ordinary artisan would have found it prima facie obvious to modify the teachings Bernstein regarding a method of treating osteopetrosis using HSCs which can differentiate into monocytes with the teachings of Kodama regarding the role of monocytes and osteoclasts in curing osteopetrosis and with the teachings of de Souza regarding the administration of monocytes for therapeutic treatment to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to substitute monocytes for the HSCs of Bernstein since Kodama teaches that it is osteoclasts, which are produced from monocytes, that are the effector in repairing bone damage resulting from osteopetrosis.
There would have been a reasonable expectation of success that monocytes could be substituted for HSCs since de Souza teaches at the time of filing that monocytes can be therapeutically administered for the treatment of disease.
Thus the cited art provides the requisite teachings and motivations to make and use the invention as claimed.
Response to Arguments
Applicant’s Arguments
Applicants argue in amendment that the combined references do not render the pending claims obvious because they do not teach or suggest all elements of the claims. In particular, the combined references fail to teach or suggest the use of the claimed monocytic cells from a healthy donor to treat the target condition per se or demonstrate efficacy for this purpose, as required under U.S. case law.
Under current case law, therapeutic methods relating to subjects "in need thereof'
comprise an intent component that must be met by the prior art. Cited references must teach or
suggest methods comprising the intent to treat the same patient populations or achieve the same
effect. In particular, Jansen v. Rexall Sundown, 342 F.3d 1329 (Fed. Cir. 2003), which follows
Rapoport v. Dement, 254 F.3d 1053 (Fed. Cir. 2001), is controlling in the present case.
The holding of Jansen v. Rexall Sundown is set forth in MPEP § 2111, which relates to
claim construction generally, and not to any particular grounds for rejection. Accordingly, it is
applicable to obviousness rejections.
Under the holding of Jansen, the preamble of claim 1 imparts an intent element to the
claim and requires that the recited method be performed for the purpose of treating osteopetrosis.
The claim therefore requires that subjects administered the recited monocytic cells from a
healthy donor have osteopetrosis per se, and not merely some condition as asserted by the
Examiner. See, e.g., the Examiner's assertion at page 5 of the Office Action that "de Souza
teaches that infusing bone marrow derived monocytes into a mouse model of chronic liver
damage... was successful in treating liver fibrosis." (emphasis added). de Souza, in this case, is the only cited reference that describes the use of monocytes as a treatment modality. However,
the bone marrow-derived monocytes of de Souza were administered to mice to observe their
effects on chronic liver damage induced by carbon tetrachloride and ethanol. Liver fibrosis is
not osteopetrosis and, indeed, none of the cited references teaches or suggests the claimed
method of administering monocytic cells from a healthy subject to treat osteopetrosis per se.
Under Jansen and Rapoport, the claims only could be obvious if the prior art teaches the
use of the recited monocytic cells from a healthy donor with the intent to treat or prevent
osteopetrosis, which plainly is not the case for de Souza, or any of the cited references.
Accordingly, the combined references fail to teach or suggest the use of the claimed
monocytic cells from a healthy donor to treat the target condition per se, as required under U.S.
case law. Applicant therefore respectfully urges reconsideration and withdrawal of the rejection.
The Examiner asserts that "[t]here would have been a reasonable expectation of success
that monocytes could be substituted for HSCs [of Bernstein] since de Souza teaches at the time
of filing that monocytes can be therapeutically administered for the treatment of disease." Office
Action, page 6. However, as described above this does not comport with current case law, as
none of the cited references teaches or suggests the administration of monocytic cells from
healthy donors to specifically treat osteopetrosis. de Souza teaches the use of monocytes to treat
chronic liver damage, and there is nothing in de Souza that would suggest the use of monocytes
to address any other disease or condition, let alone osteopetrosis.
With regard to the teachings of Bernstein and Kodama, both references employ very
different treatment modalities as compared to the claimed administration of monocytic cells from
healthy donors. The Examiner asserts that "[w]hile Bernstein does not teach specifically treating
osteopetrosis with monocytes as claimed, Bernstein does teach the ordinary artisan at the time of
filing that cells differentiated from HSCs, i.e. monocytes can be used in methods of treating
osteopetrosis." Office Action, page 11. This is not an accurate characterization of Bernstein.
As an initial matter, Applicant reiterates that Bernstein mentions osteopetrosis only once
and in a table listing ~95 other diseases and disorders "which can be treated by administering
Expanded eHSC of the of the Invention" with no reference made to treatment using any cell
differentiated from eHSCs, let alone monocytes. Bernstein, Table 2. Although Applicant appreciates that the disclosure of a reference is not limited to its examples, the examples are
pertinent to the inquiry at hand-whether one of ordinary skill in the art would have been
motivated to select the claimed treatment or prevention of osteopetrosis from a listing of nearly
95 other diseases or disorders from a reference (Bernstein) that, as acknowledged by the
Examiner, does not even mention the administration of monocytes for treating or preventing any
disease or disorder. Here, where the record is devoid of any such motivation, the obviousness
rejection should be withdrawn. The sole example in Bernstein relates to an evaluation of
"whether embryonic-derived HSPC have capacity to respond to ligand-induced Notch signaling
ex vivo, and whether Notch activation could promote expansion of engrafting cells from these
embryonic sources." Bernstein, paragraph [0256].
Moreover, with regard to the treatment modality employed in Bernstein, a person of
ordinary skill in the art would understand that the eHSC transplantation mentioned as a
possibility in Bernstein is a significantly different treatment modality as compared to the use of
differentiated monocytic cells from a healthy subject in treating a disease as demonstrated by
experimental examples in the present application. First, ex vivo expansion and maintenance of
HS Cs requires specific factors and additives. Indeed, the primary focus of Bernstein was to
search for new additives to optimize ex vivo expansion and maintenance ofHSC. See, e.g.,
Bernstein at Abstract and claim 1 (adding a notch agonist). Second, as known in the art, HSC
transplantation requires: (1) irradiation or chemotherapy to deplete host bone marrow; and (2) a
certain degree of HSC chimerism to achieve expected results in vivo. Thus, a person of ordinary
skill in the art would have no reason, motivation, or reasonable expectation of success in
substituting the HSC transplantation of Bernstein with monocytic cell administration, which does
not require bone marrow depletion or any HSC chimerism, in treating any diseases, let alone
osteopetrosis.
Furthermore, nowhere does Bernstein provide any guidance for the person of ordinary
skill in the art to correlate monocytic cell administration with desirable therapeutic effects in
treating osteopetrosis. Rather, Bernstein merely discloses that HSCs may be further
differentiated into subpopulations of cells, and HSC transplantation may be used in treating various diseases. For example, Bernstein teaches that HSCs "can differentiate into (i) myeloid
progenitor cells, which myeloid progenitor cells ultimately give rise to monocytes and
macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets,
dendritic cells, or (ii) lymphoid progenitor cells, which lymphoid progenitor cells ultimately give
rise to T-cells, B-cells, and lymphocyte-like cells called natural killer cells (NK-cells)."
Bernstein, paragraph [0008]. Additionally, as mentioned above, Bernstein discloses a long
laundry list of -95 diseases or conditions that could potentially be treated by HSC
transplantation. See Bernstein, Table 2. However, Bernstein provides no working example of
treating any disease using the HSCs. Thus, Bernstein provides no guidance whatsoever to a
person of ordinary skill in the art to reasonably predict that administering monocytic cells from a
healthy donor subject can treat or prevent osteopetrosis, as claimed.
Kodama fails to remedy the deficiencies of Bernstein. With regard to the treatment
modality, Kodama teaches the use of recombinant human macrophage colony-stimulating factor
(rhM-CSF) to address osteoclast, monocyte, and macrophage deficiencies in op/op mice. The
administration of rhM-CSF, which is a cytokine and growth factor that stimulates differentiation
of progenitor cells to mature monocytes, is similarly a very different treatment modality as
compared to the administration of monocytic cells from a healthy donor. Stimulating the
differentiation of progenitor cells in a diseased subject by administering rhM-CSF as described
in Bernstein cannot be equated with the administration of differentiated monocytic cells from a
healthy subject, as claimed. Moreover, Kodama provides absolutely no teaching or suggestion
that would have motivated a person having ordinary skill in the art to administer anything other
than rhM-CSF to address a monocyte deficiency in osteopetrosis. As Kodama states, its results
"demonstrate that injection of purified rhM-CSF is enough to cure the monocyte deficiency in
op/op mice." Kodama, page 270, second column.
None of the combinations of cited references provide any motivation to administer
monocytic cells from a healthy donor to a subject in need thereof. In summary, Bernstein lists
osteopetrosis among a laundry list of approximately 95 other diseases and disorders as
"Examples of particular hematopoietic diseases and disorders which can be treated by the Expanded eHSC of the invention," but, as acknowledged by the Examiner, does not even
mention the administration of monocytes for treating or preventing any disease or disorder.
Kodama relates to the use of rhM-CSF to stimulate progenitor cells to mature in op/op mice, but
does not disclose, teach, or suggest any cellular therapies, let alone the claimed administration of
monocytic cells from healthy donors. Although de Souza describes an administration of
monocytic cells, it is only in the context of treating chronic liver damage, not osteopetrosis.
Accordingly, for at least these reasons, the cited combination of references does not make
out a prima facie case of obviousness or provide a reasonable expectation of success for the
claimed methods. Applicant therefore respectfully urges reconsideration and withdrawal of the
rejection.
It is further required under current case law that where the prior art is purported to teach
the use of a composition for a specific purpose, a showing of efficacy is required for a finding of
obviousness as found in OSI v. Apotex.
In this case, the combined references do not teach or suggest methods comprising
administration of the claimed monocytic cells from a healthy donor to treat osteopetrosis per se,
as described in Sections A and B. Nor is there a showing of efficacy as required under Apotex.
None of the references provide any teaching or suggestion that monocytic cells from a healthy
subject could be administered to a subject in need thereof to treat or prevent osteopetrosis or that
such an administration would be effective, as demonstrated by the present application. Applicant
therefore respectfully urges reconsideration and withdrawal of the rejection.
With regard to the claimed elements that the method does not comprise hematopoietic
stem cell transplantation and wherein the method does not result in hematopoietic stem cell
chimerism, the Examiner asserts that "this would be obvious in view of the teachings of de
Souza regarding administering only monocytic cells. If only monocytic cells are administered
then no HSC transplantation or HSC chimerism will occur." Office Action, page 5. However, as
described above, there is nothing in de Souza to suggest that its use of monocytes to treat chronic
liver damage could be applied to the treatment of osteopetrosis, and there is nothing in Kodama
that would motivate a person of ordinary skill in the art to look to de Souza for an alternative
treatment modality (i.e., monocytes rather than rhM-CSF).
In addition, because the Examiner has not addressed the following arguments regarding
the unmet need that the present technology addresses, Applicant is reiterating those points here.
As noted above, the presently claimed methods do not comprise HSC transplantation or
result in HSC chimerism. Instead, the presently claimed methods seek to address problems
encountered with the use of bone marrow/RSC transplantation, which is the standard of care in early onset osteopetrosis in subjects. In particular, as described in the application, "bone
marrow/RSC transplantation ... requires irradiation or chemotherapy which carry the risk of
threatening infections and is frequently performed late in patients who already suffer severe
complications and is plagued by a -48% overall survival at 6-years." Specification, paragraph
[0087].
The claimed methods address these problems. However, none of the cited references
even acknowledge these issues. As such, the cited combination of references cannot and
does not suggest or provide a reasonable expectation of success for the claimed methods.
The present claims are directed to the use of monocytic cells from healthy donors in
treating or preventing osteopetrosis in a subject in need thereof without transplanting HSCs and
without causing HSC chimerism. As described in the application, the inventors found that
administering monocytic cells by "an appropriate regimen of transfusion can achieve expression
of a donor-derived gene by recipient osteoclasts in the absence of HSC chimerism, and in
addition that this effect can last for several months," thereby rescuing an adult-onset
osteopetrotic phenotype caused by, for example, cathepsin K deficiency. See Specification at
[0085], Figures 4A-4C and Figures 12A-C. The inventors also discovered that the claimed
methods were capable of rescuing bone development in early-onset congenital osteopetrosis in
the absence of HSC transplantation. See Specification at paragraph [0086] and Figures 4D-4G.
As noted above, these results are of clinical significance because the standard of care (bone
marrow/RSC transplantation) requires irradiation or chemotherapy and can result in HSC
chimerism. As such, the claimed technology represents a significant improvement over the cited
art, which does not even acknowledge the issues associated with the standard of care.
Examiner’s Response
While Applicant’s arguments have been fully considered they are not found persuasive.
It is maintained that the claimed method only requires one operable step, administering monocytic cells to treat osteopetrosis. In this regard, the art of record provides sufficient motivation to administer monocytes for the treatment of osteopetrosis. While Bernstein does not teach specifically treating osteopetrosis with monocytes as claimed, Bernstein does teach the ordinary artisan at the time of filing that cells differentiated from HSCs, i.e. monocytes, can be used in methods of treating osteopetrosis.
The claimed method only requires a treatment of osteopetrosis and this treatment can vary in effectiveness. In this regard Kodama teaches it was the cellular effects (via rhM-CSF) that were the effectors in their animal model. From the rejection above, Kodama importantly teaches:
“Our present study demonstrates that the deficiency in osteoclasts and monocytes in op/op mice is caused by the absence of functional M-CSF. Interestingly, osteoclasts in different bones and monocytes in peripheral blood showed different responsiveness to the rhM-CSF injections. Osteoclasts appearing in response to the rhM-CSF injections showed a distribution similar to that observed in normal mice and actively participated in physiological bone remodeling.” (pg. 272 col. 1 lines 1-8).
It is maintained that is was well known that monocytes produce osteoclasts and the teachings of Kodama provide the ordinary artisan that osteoclasts and monocytes are the effector cells for the treatment of osteopetrosis. The administered rhM-CSF only served to boost osteoclast and monocyte numbers in an osteopetrosis model with the effect being a cure of osteopetrosis. One of ordinary skill in the art would be motivated at the time of filing to administer monocytic cells as claimed for the treatment of osteopetrosis since Bernstein teaches that cells can be administered for the treatment of osteopetrosis and Kodama teaching that monocytic cells are the effector cells for treating osteopetrosis.
Thus, for the reasons above and of record the rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 DAVID A MONTANARI whose telephone number is (571)272-3108. The examiner can normally be reached M-Tr 8-6.
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DAVID A. MONTANARI
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632